The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism

BBAMCB-57868; No. of pages: 13; 4C: 2, 4 Biochimica et Biophysica Acta xxx (2016) xxx–xxx

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The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism☆ Shiu-Cheung Lung, Mee-Len Chye ⁎ School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China

a r t i c l e

i n f o

Article history: Received 26 November 2015 Received in revised form 28 December 2015 Accepted 29 December 2015 Available online xxxx Keywords: Ankyrin repeat Fatty acid Heavy metal Interactor Kelch motif Phospholipid

a b s t r a c t Acyl-CoA esters are the activated form of fatty acids and play important roles in lipid metabolism and the regulation of cell functions. They are bound and transported by nonenzymic proteins such as the acyl-CoA-binding proteins (ACBPs). Although plant ACBPs were so named by virtue of amino acid homology to existing yeast and mammalian counterparts, recent studies revealed that ligand specificities of plant ACBPs are not restricted to acyl-CoA esters. Arabidopsis and rice ACBPs also interact with phospholipids, and their affinities to different acyl-CoA species and phospholipid classes vary amongst isoforms. Their ligands also include heavy metals. Interactors of plant ACBPs are further diversified due to the evolution of protein–protein interacting domains. This review summarizes our current understanding of plant ACBPs with a focus on their binding versatility. Their broad ligand range is of paramount significance in serving a multitude of functions during development and stress responses as discussed herein. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner. © 2015 Elsevier B.V. All rights reserved.

1. Introduction In eukaryotes, acyl-CoA synthetase activates long-chain fatty acids (FAs) by the attachment of coenzyme A (CoA) via a thioester linkage [1]. The resulting acyl-CoA esters are crucial for the transport and intermediary metabolism of FAs such as complex lipid assembly, β-oxidative degradation, protein acylation and derivation into very-long-chain (VLC) variants [2–4]. Together with their involvement in regulating enzyme activities [5–7], vesicular trafficking [8,9], gene expression [10–12] and intracellular signaling [13,14], the abundance of acyl-CoA esters is tightly controlled and they scarcely exist in free, unbound form [15,16]. Despite an estimation of cellular acyl-CoA concentration at several hundred μM, free molecules in the cytosol are maintained at b10 nM due to their association with membrane lipids and binding proteins [15,17]. Although acyl-CoA esters are non-specific ligands of ubiquitous nonenzymic proteins such as FA-binding proteins [18–20], sterol carrier protein-2 [21,22] and lipid-transfer proteins (LTPs) [23,24], their higher affinity to acyl-CoA-binding proteins (ACBPs) support these as the predominant carriers [20]. Initially, the first ACBP was reported as a neuromodulator that inhibits binding of an anxiolytic agent, diazepam, to its receptors on synaptic membranes in rat brain [25,26]. Some mammalian ACBPs

☆ This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner. ⁎ Corresponding author at: School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China. E-mail addresses: [email protected] (S.-C. Lung), [email protected] (M.-L. Chye).

were co-recognized as cell growth modulators [27], steroidogenesis stimulators [28] and insulin secretion inhibitors [29]. The discovery of acyl-CoA-binding (ACB) functions of ACBPs [30,31] prompted sequence homology searches in other genomes, yielding orthologs from virtually all eukaryotes and some pathogenic eubacteria [32,33]. Multiple isoforms exist in most eukaryotes examined except fungi [33,34]. Despite the classical definition as a small (ca. 10-kDa) protein, widely regarded as the prototypic form, ACBPs can also appear as large multi-domain proteins [16,33–35]. In mammals, ACBPs are grouped by tissue specificities into (i) the commonly expressed ACBP/diazepam-binding inhibitor (DBI)/endozepine which was first identified in bovine liver (L-ACBP); (ii) testis-specific endozepine-like protein (T-ACBP); and (iii) brainspecific DBI from duck and frog brains (B-ACBP) [32–34,36]. In contrast, classification of plant ACBPs is based on their molecular mass and domain architecture [37–40] (Fig. 1). Each of the four classes (namely small, ankyrin-repeat, large and kelch ACBPs) is well represented, for instance, by at least one member in 12 of the 13 higher plant species investigated [37,41]. Apparently, this classification scheme may not be applicable to non-plant ACBPs which exhibit considerable diversity and flexibility in protein domain architecture [16]. Besides the four distinct domains (i.e. Golgi dynamics, Herpes DNAp, ankyrin and enoylCoA hydratase) present in human ACBPs, other mammalian forms also contain haemolytic-, microcephalin-, GVQW- and homeo-domains with further diversity in the animal phyla [16]. Apart from classification, plant ACBPs differ from non-plant counterparts in ligand-binding specificities. In animals, although the identity of the major contributing proteins for binding acyl-CoA esters had been a subject of debate, a consensus was reached on the high-affinity binding

http://dx.doi.org/10.1016/j.bbalip.2015.12.018 1388-1981/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

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Fig. 1. Domain architecture of Classes I–IV ACBPs from various higher plant species. For alignment with the Conserved Domain Database (CDD) collection, ACBP sequences from A. thaliana, B. napus, V. vinifera, V. fordii and O. sativa were submitted to the NCBI protein BLAST search at http://blast.ncbi.nlm.nih.gov/Blast.cgi/. The identified domains and motifs include acyl-CoAbinding domain (cd00435) as annotated in blue, ankyrin-repeat domain (cd00204) in red, and kelch motif (pfam01344, 07646, 13415, 13418 and 13854) in green, and the predicted transmembrane domains are shown in yellow. Sorting sequences include signal peptides (in grey) and a peroxisomal-targeting signal (in purple). The total amino acid numbers are indicated in parentheses. The protein sequences are retrievable under the GenBank accession numbers as indicated for BnACBPs or as follows: AtACBP1 (AED96361), AtACBP2 (AEE85391), AtACBP3 (AEE84874), AtACBP4 (AEE74237), AtACBP5 (AED93708), AtACBP6 (AEE31396), VvACBP (ADK56449), VfACBP3A (AFZ62128), VfACBP3B(AFZ62129), OsACBP1 (BAG86980), OsACBP2 (BAG86809), OsACBP3 (ABF97253), OsACBP4 (BAF16206), OsACBP5 (BAG93201) and OsACBP6 (ABF99748).

of animal ACBPs exclusively to long-chain acyl-CoA esters (but not to FAs, phospholipids, lysophosphatidylcholine (lysoPC), cholesterol or other ligands tested), distinguishing this protein family from other non-specific binding proteins [15,23,30,33,42,43]. On the contrary, the

past decade has seen the emergence of a broader ligand range of plant ACBPs, from diverse species of acyl-CoA esters, phospholipids to heavy metals. The evolution of protein–protein interacting domains in some subclasses further diversifies the nature of plant ACBP interactants. In

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

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this review, we introduce different classes of plant ACBPs with an emphasis on their binding versatility, which is dictated by distinct protein structures as discussed. The broad range of binding partners for plant ACBPs is perhaps linked to their specific functions in development and stress responses. 2. The four classes of plant ACBPs The past years have seen the six-membered family of Arabidopsis thaliana ACBPs characterized extensively in this laboratory [41,44,45]. The six homologs in rice (Oryza sativa) have also been investigated recently [37,38,46], and ACBPs were distinguished into four classes using our classification criteria based on molecular mass and domain architecture [37,44] (Fig. 1). These criteria have also been implemented in studies on ACBPs from tung tree (Vernicia fordii) [47], grape (Vitis vinifera) [48] and oilseed rape (Brassica napus) [39,40] (Fig. 1). 2.1. Small ACBPs (Class I) Class I members are the prototypic form of low-molecular-mass (ca. 10-kDa) cytosolic ACBPs (Fig. 1), which are highly conserved amongst eubacteria, fungi and higher eukaryotes [32–34]. After discovery of the first plant ACBP from oilseed rape [5,49], a number of sequences encoding Class I representatives have been identified and characterized in higher plants, including Arabidopsis [50,51], foxglove (Digitalis lanata) [52], rice [37,53], tung tree [47] and physic nut (Jatropha curcas) [54]. Given the high expression of Class I BnACBP in developing embryos, flowers and cotyledons, pioneering studies were centered on its role in storage lipid biosynthesis [49]. During embryogenesis, Class I BnACBP stimulates carbon flux into FA synthesis by alleviating the inhibitory effect of acyl-CoA esters on plastidial glucose-6-phosphate metabolism [55,56]. For the assembly of triacylglycerols (TAGs), Class I BnACBP enhances the activities of enzymes catalyzing all acyl-CoA-dependent acylation steps in the Kennedy pathway [57], including glycerol-3-phosphate acyltransferase [5], lysophosphatidic acid acyltransferase [58] and diacylglycerol acyltransferase [6,7]. Class I BnACBP also promotes acyl editing for the enrichment of polyunsaturated acyl-CoA esters in the cytosolic pool by stimulating acylCoA:lysoPC transferase activity (LPCAT) [59,60]. Overall, the importance of Class I BnACBP on seed oil formation was deduced by observations in its 12-fold elevation during seed maturation, coinciding with peak of storage lipid accumulation [50] and its dramatic decline in desiccating seeds at maturity [5]. In Arabidopsis, AtACBP6 (10.4-kDa) is the sole Class I member [44]. It cooperates with two other cytosolic Class IV members, AtACBP4 and AtACBP5, in pollen, seed and seedling development [61, 62]. Observations in cold-inducible AtACBP6 accumulation and freezing resistance in AtACBP6-overexpressors indicated its role in low temperature tolerance [51,63]. In rice, the Class I OsACBP1 (10.2-kDa), OsACBP2 (10.3-kDa) and OsACBP3 (17.7-kDa) are the smallest of six rice ACBPs [37]. The higher molecular mass of OsACBP3 is attributed to an extra 64-residue C-terminal extension which may harbor a sorting signal necessary for protein localization to some irregular membranous and randomly scattered punctate in addition to the cytosol [38]. Quantitative real-time polymerase chain reactions (qRT-PCR) revealed a steady expression of OsACBP1 contrasting to the up-regulation of OsACBP3 at anthesis and the peaking of OsACBP2 at the dough stage, suggesting nonredundant functions for the three during reproduction [37]. 2.2. Ankyrin-repeat ACBPs (Class II) Class II is represented by ankyrin-repeat ACBPs (Fig. 1), which are common in Eukarya. Of the 4721 retrievable eukaryotic and eubacterial ACBP sequences, the majority (~70%) possess solely an ACB domain whilst 10% is accompanied by a C-terminal ankyrin-repeat domain, which represents the most dominant subdomain in the ACBP family [16]. The Arabidopsis genome encodes Class II AtACBP1 (37.5-kDa) and AtACBP2 (38.5-kDa) [64–71], whilst rice has one member (36-kDa

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OsACBP4) [37]. A recent computational prediction of a Class II BnACBP conformation revealed a conserved ankyrin-repeat structure, which features α-helical interactions stabilizing an inner core and β-hairpin surfaces potentially for protein–protein interaction [39]. An N-terminal transmembrane helix directs AtACBP1 and AtACBP2 to the plasma membrane and endoplasmic reticulum (ER) [66,67]. The two homologs share 71% amino acid sequence identity [72] and a redundant role in embryogenesis [73]. AtACBP1 also functions in stem cuticle formation [74] and cold tolerance [75], and AtACBP2 in drought resistance [70]. In addition, the ankyrin repeats mediate protein–protein interactions for both isoforms in hypoxic [76] and heavy-metal [68,69,77] stresses, and AtACBP1 further participates in abscisic acid (ABA) signaling [71]. Contrary to its Arabidopsis counterparts, OsACBP4 is an ER-resident protein with no evidence yet for its sorting to the plasma membrane [38]. Resembling AtACBP2 [70], OsACBP4 may play a potential role in drought response from its inducible expression upon high salinity or drought treatment and the corresponding presence of putative cis-elements such as the DRE/CRT (dehydration-responsive element/C-repeat) at its 5′-flanking region [37]. 2.3. Large ACBPs (Class III) In Class III, an ACB domain is uniquely located at the C-terminus [37, 78] (Fig. 1). Class III ACBPs are generally larger despite a broader range in molecular masses. For instance, the sole members in Arabidopsis (AtACBP3) [79] and rice (OsACBP5) [37] are 39.3 and 61.2 kDa, respectively, whereas various homologs in oilseed rape, tung tree and grape vary from 31.2 to 41.9 kDa [39,47,48]. Except for two of the four BnACBPs, the N-termini of these Class III members feature a membrane-spanning region [37,39,47,48,79,80], responsible for ER localization as visualized by green fluorescent protein (GFP) fusions with AtACBP3 [80], OsACBP5 [38,46] and VfACBP3 [47]. Besides the localization of AtACBP3:GFP at the periphery of the ER/Golgi complex [80], both AtACBP3:GFP and AtACBP3:DsRed displayed extracellular secretion mediated by a cleavable signal peptide that partially overlapped with the transmembrane domain [79,80]. Consistently, Class III VvACBP:GFP was visualized at the periphery of onion epidermal cells [48]. The endomembrane and apoplastic localization of AtACBP3 were linked to its roles in pathogen defense [78,81], hypoxic response [82], and starvation-induced and age-dependent leaf senescence [80,83]. On the other hand, the conserved signal peptides of VfACBP3A and VfACBP3B did not guide GFP fusion proteins to the secretory pathway [47], resembling the non-secreted ER-associated OsACBP5 [38]. The inconsistent localization patterns and potentially significant divergence of Class III ACBPs in evolution may indicate that they have different functions [47]. Nonetheless, it appears that multi-members share common roles in defense. In transgenic Arabidopsis, the overexpression of Class III AtACBP3 or VvACBP enhanced resistance to the bacterial pathogen Pseudomonas syringae [48,78]. The latter also promoted tolerance to the hemibiotrophic fungal pathogen Colletotrichum higginsianum [48]. Consistently, AtACBP3 was up-regulated by P. syringae, the necrotrophic fungus Botrytis cinerea and the fungal elicitor arachidonic acid [78,81], and OsACBP5 by the rice blast fungus Magnaporthe grisea [37]. 2.4. Kelch-ACBPs (Class IV) Apart from the ankyrin repeats in Class II, another protein–protein interactive structure, kelch, is found in Class IV ACBPs (Fig. 1). The vast majority of kelch-ACBPs are from Plantae, although two homologs also exist in the phytoplankton Emiliania huxleyi [16]. The predicted conformation of a Class IV BnACBP suggested an over-representation of coils and helices that deviated from the usual β-propeller structures of kelch motifs, implicating the importance of experimental investigations in the future [39]. Besides the ACB domain and kelch motif, most of the kelch-ACBPs contain additional protein domains of dissimilar functions [16], accounting for the high molecular mass of all Class IV members. For instance, the two members in Arabidopsis (AtACBP4 and AtACBP5), the

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

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sole member in rice (OsACBP6) and the eight homologs in oilseed rape range from 71.0 to 73.2 kDa [37,39,44]. Fluorescent protein tagging with AtACBP4 and AtACBP5 showed cytosolic signals [84], in agreement with the predicted cytoplasmic localization of all Class IV BnACBPs [39]. On the other hand, OsACBP6 is the only confirmed peroxisomal ACBP in plants thus far [38], consistent with a predicted peroxisomal-targeting signal (Fig. 1), although 56.6-kDa ACBP-like proteins have been identified in peroxisomal proteomes of rat liver and mouse kidney [85,86]. While OsACBP6 functions in β-oxidation of FAs and their derivatives and in the synthesis of jasmonate [38], the cytosolic AtACBP4 and AtACBP5 are associated with the biosyntheses of membrane galactolipids and phospholipids [84,87], in addition to their combinatory role with Class I AtACBP6 in pollen, seed and seedling development [61, 62]. The function of AtACBP4 in defense signaling emerged from its interaction with an ethylene-responsive element binding protein [88] and its role in the generation of systemic acquired resistance signals [89]. 3. Protein structures implicate ligand diversity Over the past two decades, solution structures of small ACBPs from cow [90–93] and yeast [93] have been analyzed by nuclear magnetic resonance (NMR) spectroscopy, and the 10-kDa ACBPs from cow [94], Plasmodium falciparum [94], armadillo [95] and man [96] have been crystallized and solved (Fig. 2). Consistent with the high sequence conservation, all of them are folded almost identically into a four α-helix-bundle structure in an up-down-down-up arrangement [90–96]. The resolved structure of bovine ACBP in complex with palmitoyl-CoA esters revealed that the acyl chain is buried in a hydrophobic groove and sealed from the aqueous environment by the coenzyme A headgroup [34]. The affinity for a ligand that can be accommodated in the single binding site of bovine ACBP depends on the acyl chain length, preferably saturated or unsaturated acyl-CoA esters with 14–22 carbon atoms [33,42]. In this model, the precise mode of interaction with the acyl chain, the coenzyme A headgroup and 3′-phosphate on the ribose moiety of a ligand excludes the binding of bovine ACBP to other lipidic compounds, implicating that the protein structure dictates ligand specificity [42]. On the other hand, a slight conformational difference between isoforms allows for some degree of ligand selectivity. Amongst the deposited ACBP structures, the first loop between the A1 and A2 helices and the next (prior to the A3 helix) are loosely defined [33]. For instance, P. falciparum ACBP when compared to its mammalian homologs has two extra residues in the first loop compared to mammalian homologs that may force a ligand into unique conformation [94]. The terminal carbon of this acyl chain is fitted into a binding pocket in PfACBP [94]. In comparison, the binding tunnel of bovine ACBP accommodates a chain length longer than 16 carbon atoms [94]. Accordingly, PfACBP has a preference for shorter chain lengths, fulfilling a greater demand for myristoyl-CoA esters in the biosynthesis of di-14:0-glycosylphosphatidylinositol-anchored proteins for protection [16,94]. Despite the presence of the same binding tunnel,

human ACBP adopts a novel binding model [96]. In contrast with monomers in both holo- and apo-forms and a 1:1 stoichiometry of proteinligand interaction for most ACBPs, the holo-structure of human ACBP had two ligands bound to a homodimer with the binding of a myristoyl-CoA molecule across two proteins [96]. The reversed direction in bound acyl moiety differed from the classic monomeric mode in binding [96]. Whilst the association of an acyl-CoA molecule to human ACBP induces only minor structural changes close to the binding pocket [96], Moniliophthora perniciosa ACBP shifted from monomeric to dimeric state upon ligand binding [97]. This 14.4-kDa isoform differed from other small ACBPs by a C-terminal extension which folded into the fifth αhelix constituting a topology distinct from the typical four-helix bundle [97]. Its unique ligand-inducible dimerization and extensive first loop (between A1 and A2), the longest amongst ACBP structures, may account for its preference for long-chain ligands (up to C20), while acyl-CoA esters with greater than 20 carbon atoms remain to be tested [97]. To date, no X-ray crystal or NMR structure of any plant ACBP has been published, and the predicted three-dimensional conformations of ACBPs from Arabidopsis, tung tree and oilseed rape were based on homology modeling [39,47,79]. Although the model prediction for Class I BnACBP, built from the crystal structure of liganded human ACBP with 48% identity and 95% coverage, illustrated a four-α-helical structure, the conserved up-down-down-up topology of non-plant ACBPs was not evident [39]. On the contrary, this up-down-down-up topology has been predicted in Class III members from all three species, whilst non-ACB regions remain highly variable [39,47,79]. For instance, a long stretch of random coil connects N-terminal α-helices to the ACB domain forming a narrow cleft in VfACBP3A, while VfACBP3B does not have this cleft or a long random coil [47]. The predicted three antiparallel β-sheets in AtACBP3 is also absent from both tung homologs [47]. In Class II, greater discrepancy is found amongst predicted structures of ACB domains from BnACBP, AtACBP1 and AtACBP2, which are composed of six, four and three α-helices, respectively [47,79]. Although AtACBP1 and AtACBP2 are Class II homologs, the higher structural resemblance of AtACBP1 to Class III AtACBP3 than to AtACBP2 is in line with their related ligand preferences, substantiating a close link between protein structure and function [79]. Besides, site-directed mutagenesis demonstrated that some conserved residues of AtACBPs are crucial for binding specific ligands but mutation of the equivalent sites in other isoforms did not produce an adverse effect [35,65,79], suggesting that the structural determinants that define functional specificity are not conserved in all ACBPs, and that the structural and biochemical data attained from an isoform should not be over-interpreted in different classes of plant ACBPs. 4. Acyl-CoA binding To provide the first insight into the ligand specificities of various plant ACBPs in vitro, their cDNAs were expressed in Escherichia coli for the production of recombinant (r) proteins, including rAtACBP1 [68,71–73,75,

Fig. 2. Representative structures of liganded ACBPs. Crystal structures of liganded ACBPs from Homo sapiens (A) and Plasmodium falciparum (B) were obtained from the RCSB Protein Data Bank (PDB; http://www.rcsb.org/) under the PDB ID codes 2CB8 [96] and 1HBK [94], respectively.

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

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79], rAtACBP2 [65,68–70,73,98], rAtACBP3 [79,80,82], rAtACBP4 [35,61, 84,87], rAtACBP5 [35,61,79,84,87], rAtACBP6 [50,51,61], rOsACBP1 to rOsACBP6 [37,38], Class I rBnACBP [7,59] and rVfACBP3s [47]. Subsequent binding tests against a variety of potential interactants by in vitro techniques such as Lipidex-1000, gel- and filter-binding assays indicated substantial difference in ligand preferences of these rACBPs (Table 1). Quantitatively, binding kinetics were compared using isothermal titration calorimetry (ITC) and microscale thermophoresis (MST) (Table 1). To further validate in vitro data and provide physiological relevance in planta, acyl-compositional changes were profiled in different tissues upon manipulation of ACBP expression, as elucidated using transgenic Arabidopsis overexpressors, RNA interference (RNAi) and/or mutant lines of all AtACBPs except AtACBP5 (Table 2). Recently, the overexpression of ACBPs from other species in transgenic Arabidopsis not only demonstrated functional conservation of the plant ACBP family but also unraveled specific roles in certain species [7,47,59,60]. A conditional change in acyl-lipid profiles of Arabidopsis transgenic overexpression or mutant lines, subjected to freezing [51,63,75], darkness [80], abscisic acid (ABA) [71] or submergence [82], has indicated roles in signal transduction or stress responses. Concomitantly, phenotypic aberrance of the Arabidopsis lines has further solidified evidence for developmental or stress-responsive functions of a plant ACBP tested, in accordance with its specific binding of long-chain, VLC or polyunsaturated acyl-CoA esters as summarized below. 4.1. Long-chain acyl-CoA esters In plastids, long-chain FAs are synthesized de novo via sequential reactions catalyzed by stromal enzymes including acetyl-CoA carboxylase and FA synthetase [99]. These nascent FAs are used to generate complex lipids plastidially via the prokaryotic pathway [100–101] or extraplastidially via the eukaryotic pathway [102,103]. During their export into the cytosol,

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FAs are converted into the CoA-activated form by acyl-CoA synthetase at the outer membrane of the plastidial envelope [104,105]. Due to their susceptibility to hydrolytic degradation and their detergent-like properties that deteriorate cellular membranes, long-chain acyl-CoA esters are sequestered in a cytosolic pool by ACBPs [20,50,106,107]. Related to this ubiquitous function, cytosolic ACBPs from Arabidopsis [35,51,61,87], rice [37] and oilseed rape [59] bind C16 and C18 acyl-CoA esters with high affinities (Table 1). To these ligands, ITC revealed that rAtACBP6 exhibited much higher affinities than rAtACBP4 and rAtACBP5 [61]. Site-directed mutagenesis further indicated that any single substitution of the eight selected residues within the ACB domain of rAtACBP4 and rAtACBP5 impaired binding to oleoyl-CoA esters [35]. Apart from the ligand-binding function, Class I BnACBP stimulated the activities of TAG biosynthetic enzymes in vitro [5–7,58]. Seed-specific production of this BnACBP in transgenic Arabidopsis increased palmitoyl-, stearoyl- and arachidoyl-CoA levels during seed development, whilst seed oleoyl-CoA content declined 20 days after flowering [60]. Consistently, cotyledonary-staged embryos of the atacbp6 mutant contained more oleoyl-CoA ester than the wild type [61]. The atacbp6 mutant seeds appeared normal unless the other two cytosolic isoforms AtACBP4 and AtACBP5 were also depleted in a triple mutant, which set lighter seeds, confirming overlap in their function during seed development [61]. In rosettes, AtACBP6 was down-regulated in light whereas AtACBP4 and AtACBP5 were up-regulated [87,108]. During the active phase of FA synthesis, the light-regulated AtACBP4 and AtACBP5 may shuttle nascent acyl chains from plastids to the ER [87, 108], as their expression patterns coincided with those of the genes encoding an ω-3 FA desaturase [109] and acetyl-CoA carboxylase [110, 111]. The diurnal change in leaf lipid composition also suggested an increase in oleoyl chains during the day and its decline at night [112,113]. In Arabidopsis seedlings, the diurnal patterns of acyl-CoA levels and gene expression related to lipid metabolism were altered in an arrhythmic line (cca1lhy double mutant) with a malfunctioning biological clock

Table 1 Interactants of plant ACBPs. Class

I

Isoform

By quantitative methods

14:0, 16:0, 18:0, 18:1, 18:2, 18:3 (Kd in nM range)

OsACBP2

16:0, 18:1, 18:2, 18:3, 20:4 16:0, 18:1, 18:2, 18:3 18:3

OsACBP3

18:3

BnACBP AtACBP1

18:1, 18:2, 18:3 18:1, 18:2, 18:3, 20:4 16:0, 18:2, 18:3, 20:4

AtACBP2

III

OsACBP4

16:0, 18:2, 18:3

AtACBP3

18:1, 18:2, 18:3, 20:4 16:0, 18:3

OsACBP5

IV

Phospholipids

VfACBP3A VfACBP3B AtACBP4 AtACBP5 OsACBP6

18:1, 20:4 18:1, 20:4 16:0, 18:1, 18:2, 18:3 16:0, 18:1, 18:2, 18:3 18:2, 18:3

Heavy metals

Protein interactors

References

a

By Lipidex assays AtACBP6 OsACBP1

II

Acyl-CoA esters

18:1, 18:2, 18:3, 24:0, 25:0, 26:0 (Kd in μM range)

18:2, 20:0, 22:0, 24:0 (Kd in nM range)

14:0, 16:0, 18:0, 18:1, 18:2, 18:3 (Kd in μM range) 14:0, 16:0, 18:0, 18:1, 18:2, 18:3 (Kd in μM range) 18:3 (Kd in μM range)

Di 16:0-, 18:0-, 18:1- and 18:2-PC

[51,61]

Di 18:0- and 18:1-PA; Di 18:0-, 18:1- and 18:2-PC Di 18:0- and 18:1-PA; Di 18:0-, 18:1- and 18:2-PC Di 18:0- and 18:1-PA; Di 18:0-, 18:1- and 18:2-PC

[37,38]

Di 16:0-, 18:0- and 18:1-PA; Di 18:1- and 18:2-PC 16:0-lysoPC; Di 18:1- and 18:2-PC

[37,38] [37,38]

Pb(II) Pb(II); Cd(II); Cu(II)

AREB1, PLDα1, RAP2.12 EBP (RAP2.3), AtFP6, LYSOPL2, RAP2.12

Di 16:0-, 18:0- and 18:1-PA; Di 18:0-, 18:1- and 18:2-PC Di 16:0-, 18:0-, 18:1- and 18:2- PC; Di 16:0-, 18:0-, 18:1- and 18:2- PE Di 18:0- and 18:1-PA; Di 18:0-, 18:1- and 18:2-PC

Di 18:1- and 18:2-PC

[59] [68,71–75,77,79,176] [35,65,68,69,73,77]

[37,38] [79,80,82] [37,38]

Pb(II)

DGAT1, DGAT2 DGAT1, DGAT2 EBP (RAP2.3)

[47,171] [47,171] [35,61,87,88,169]

Di 18:1- and 18:2-PC

[35,61,87]

Di 18:0- and 18:1-PA; Di 18:0-, 18:1- and 18:2-PC

[37,38]

AREB1, ABSCISIC ACID-RESPONSIVE ELEMENT BINDING PROTEIN1; DGAT, DIACYLGLYCEROL ACYLTRANSFERASE; EBP, ETHYLENE-RESPONSIVE ELEMENT BINDING PROTEIN; FP6, FARNESYLATED PROTEIN6; Kd, dissociation constant; LYSOPL2, LYSOPHOSPHOLIPASE2; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PLDα1, PHOSPHOLIPASE Dα1; RAP, RELATED TO APETALA. a The binding affinities of AtACBP3 were determined by microscale thermophoresis and that of other ACBPs by isothermal titration calorimetry.

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

6

Class

Arabidopsis line

Sample source

Method

Acyl-lipid compositional change in comparison to the wild type Increase

I

35S::AtACBP6

atacbp6

phaP::BnACBP

5-Week-old rosettes after 3-day acclimation at 4 °C and 2-h freezing at −8 °C Detached flowers subjected to 3-day acclimation at 4 °C and 1-h freezing at −7 °C 5-Day-old seedlings Cotyledonary-staged embryos 4-Week-old leaves Developing and mature seeds

phaP::OleoH3P:BnACBP Developing and mature seeds

II

35S::AtACBP1

5-Week-old rosettes after 3-day acclimation at 4 °C and 2-h freezing at −8 °C 5-Week-old rosettes Germinating seeds with or without 1 μM ABA treatment 12-Day-old seedlings with 100 μM ABA treatment

atacbp1

7-Week-old siliques 5-Week-old rosettes after 3-day acclimation at 4 °C and 2-h freezing at −8 °C Germinating seeds with or without 1 μM ABA treatment

AtACBP2-RNAi III

35S::AtACBP3

[51] [63] [61] [61] [89]

20:1- and 22:1-CoA in 15–20 DAF seeds; 16:0-, 18:0-, 20:0- and 20:1-FA in mature seeds 18:3- and 20:0-CoA in 10 DAF seeds; 18:3- and 20:1-CoA in 15 DAF seeds; 18:1-CoA in 20 DAF seeds; 18:0-, 20:0- and 20:1-FA in mature seeds 34:4-, 36:4-, 36:5, 38:4-, 40:3- and 40:4-PC

[59,60] [60]

[75] [71,75] [71]

ESI-MS/MS

32:0-PA without treatment; 36:3- and 36:4-PA with 12-h ABA treatment 32:0- and 36:2-PA without treatment; 32:0-, 34:4- and 34:6-PA with 3-h ABA treatment C29 alkane, secondary alcohol and ketone, and C28- and C30-OH in cuticular wax; 18:1- and 18:2-DCA and 18:2 ω-hydroxyl FA of cutin monomers 34:3-PC, PE and PI; 34:4-PG; 36:6-PC and PE 18:1- and 18:2-FAs in siliques; 18:2-FA in roots 36-2, 36:4- and 36:5-PE and PC in 6-week-old and dark-treated 3-week-old rosettes

[71]

42:2- and 42:3-PS; 22:0-, 22:1-, 24:0-, 24:1-, 26:0- and 26:1-GIPC 34:2-, 34:3- and 36:6-PE 16:0-, 18:1- and 18:2-DCA of cutin monomers

[82]

Rosettes at 2–3 weeks post-anthesis 4-Week-old roots and siliques 3- and 6-week-old rosettes

LC–MS/MS 34:2-PC, PE, PI and PG, and 36:4- and 36:5-PC and PE GC-FID 20:3- and 22:0-FA in siliques; 18:3-FA in roots ESI-MS/MS 34:2-, 34:3- and 36:6-PE in 3-week-old rosettes; 34:2-, 34:3-, 36:4- and 36:5-PA in 6-week-old and dark-treated 3-week-old rosettes ESI-MS/MS

3-Week-old rosettes 4-Week-old leaves

32:0-, 34:2, 34:3-, 34:4-, 36:2-, 36:3-, 36:4-, 36:5-, 36:6-, 38:2-, 38:3-, 38:4-, 38:5-, 38:6-, 40:4- and 40:5-PC 34:6- and 36:5-PA

ESI-MS/MS 34:2-, 34:3-, 34:6-, 36:2-, 36:3-, 36:5- and 36:6-PA ESI-MS/MS 34:2-, 34:3-, 36:2- and 36:3-PA without treatment; 34:1-, 34:4and 36:4-PA with 12-h ABA treatment ESI-MS/MS 32:0- and 34:6-PA with 1-h ABA treatment; 34:2-, 36:3-, 36:4-, 36:5- and 36:6-PA with 3-h ABA treatment RP-HPLC 18:0-CoA; 34:3-, 34:6- and 36:6-MGDG; 34:3- and 34:6-DGDG; 36:4-, 38:4-, 38:5- and 38:6-MGDG; 36:4-, 36:5-, 38:4- and 34:3- and 36:6-PC 38:5-DGDG; most polyunsaturated species of PC, PE and PI ESI-MS/MS 34:2-, 34:4-, 36:2-, 36:4-, 36:5-, 38:3-, 38:4-, 38:5- and 40:4-PC 32:0-, 34:3-, 34:4-, 36:5- and 36:6-PA

ESI-MS/MS GC-FID; GC–MS

AtACBP3-RNAi

3-Week-old rosettes 4-Week-old rosettes submerged under light

At2S4P::VfACBP3A atacbp4

Mature seeds 5-Week-old leaves

ESI-MS/MS GC–MS 16:0- and 18:0-FA, C29-, C31- and C33-alkane, and C28- and C32-OH in cuticular wax ESI-MS/MS 42:2- and 42:3-PS; 22:0-, 22:1-, 24:0-, 24:1-, 26:0- and 26:1-GIPC ESI-MS/MS ESI-MS/MS 42:2- and 42:3-PS; 22:0-, 22:1-, 24:0-, 24:1-, 26:0- and 26:1-GIPC GC-FID Eleostearic acid when co-expressed with VfFADX ESI-MS/MS

4-Week-old leaves

GC–MS

4-Week-old rosettes submerged under light

IV

ESI-MS/MS 34:2-, 34:3-, 34:4-, 36:2-, 36:3-,36:4-, 36:5-, 36:6-, 38:4- and 38:5-PC; 34:3-, 34:5-, 34:6-, 36:4-, 36:5- and 36:6-MGDG RP-HPLC 18:1- and 18:2-CoA LC–MS/MS 18:1-CoA GC–MS 16:0- and 18:0-FAs, C29-, C31- and C33-alkane, and C28- and C32-OH in cuticular wax; 18:1-DCA of cutin monomers GC–MS 16:0- and 18:0-CoA in 15–20 DAF seeds; 18:2- and 18:3-FA in mature seeds GC–MS 18:0- and 18:1-CoA in 10 DAF seeds; 16:0-, 18:0- and 20:0-CoA in 15 DAF seeds; 16:0- and 20:0-CoA in 20 DAF seeds; 18:2-FA in mature seeds ESI-MS/MS

12-Day-old seedlings with or without 100 μM ABA treatment 6-Week-old stems

4-Week-old rosettes submerged under light atacbp3

ESI-MS/MS 34:2-, 34-3-, 36:2-, 36:3-, 36:4-, 36:5- and 36:6-PA

References Decrease

16:0- and 18:0-FAs, C29-, C31- and C33-alkane, and C28- and C32-OH in cuticular wax

[71] [73] [75]

[71] [74]

[98] [98] [80]

[80] [89] [82]

34:2-, 34:3- and 36:6-PE

34:1-, 34:2-, 34:3-, 34:4-, 34:6-, and 36:3-MGDG; 34:2-, 34:3-, 34:4-, 34:5-, 34:6- and 36:6-DGDG 16:0-, 18:1- and 18:2-DCA of cutin monomers

[80] [82] [47] [84] [89]

ABA, abscisic acid; At2S4P, promoter of Arabidopsis 2S4 albumin seed storage protein; DAF, days after flowering; DCA, dicarboxylic acid; DGDG, digalactosyldiacylglycerol; ESI, electrospray ionization; FA, fatty acid; FID, flame ionization detector; GC, gas chromatography; GIPC, glucosylinositolphosphorylceramide; LC, liquid chromatography; MGDG, monogalactosyldiacylglycerol; MS, mass spectrometry; OleoH3P, modified OLEOSIN1; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosophatidylserine; RP-HPLC, reversed-phase high performance liquid chromatography; VfFADX, tung bifunctional fatty acid conjugase/desaturase.

S.-C. Lung, M.-L. Chye / Biochimica et Biophysica Acta xxx (2016) xxx–xxx

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

Table 2 Changes in acyl-lipid composition of ACBP overexpression, RNAi and mutant lines of Arabidopsis.

S.-C. Lung, M.-L. Chye / Biochimica et Biophysica Acta xxx (2016) xxx–xxx

[114]. Yet, it remains to be investigated as to whether the light-dark regulation of cytosolic AtACBPs in leaves is related to seed oil biosynthesis. Apart from complex lipid formation, Class I BnACBP is involved in the modification of long-chain acyl-lipid composition of seeds [59,60]. By acyl editing, the oleoyl moiety esterified to phosphatidylcholine (PC) can be desaturated into linoleoyl and linolenoyl derivatives [115– 118]. LPCAT releases the acyl chain from PC and vacates the site for another oleate in the next round of desaturation, leading to accumulation of polyunsaturated acyl-CoA esters in the cytosolic pool [119,120]. As rBnACBP enhanced such acyl exchange reaction in vitro, the expression of this protein in transgenic Arabidopsis seeds enriched polyunsaturated FAs at the expense of eicosenoic acid and saturated FAs [59,60]. The complementary function of the three cytosolic AtACBPs in lipid biosynthesis was not limited to seed development [62]. In developing pollen, lipid is also actively produced to form structural components such as tryphine coating the sporopollenin exine surface and carbon reserves as storage TAG and intracellular membranous structures [121– 124]. In Arabidopsis, disruption of oil body biogenesis in a double knockout of two major TAG-biosynthetic enzymes resulted in sterile pollen [125]. Similarly, mutation of ATP-BINDING CASSETTE TRANSPORTER G26 (ABCG26) affected secretion of lipidic sporopollenin precursors onto the surface of developing microspores leading to the absence of exine and reduced male fertility [126,127]. Sporopollenin- and exine-less pollen were also observed after mutation of a gene encoding ACYL-COA SYNTHETASE5, which exhibited a substrate preference for oleoyl-CoA esters [128–130]. A triple mutant depleted of the three cytosolic AtACBPs exhibited reduced germination activity of pollen, which displayed a smoother surface, fewer oil bodies and irregular bacula and tryphine, suggesting that the high affinities of AtACBP4, AtACBP5 and AtACBP6 to long-chain acyl-CoA esters are of pertinence to lipid biosynthesis in both seeds and pollen [62]. Long-chain acyl transport by plant ACBPs is not only confined to lipid biosynthesis but also extends to lipid catabolism. To mobilize carbon reserves from storage lipids, lipase-released long-chain FAs are activated into CoA-esters and β-oxidized into acetyl units, which are then further metabolized into succinate via the glyoxylate cycle [131–133]. For this reaction, FAs are imported into peroxisomes by an ABC transporter known as COMATOSE (CTS), PEROXISOMAL ABC TRANSPORTER1 (PXA1) or PEROXISOME DEFICIENT3 (PED3), mutation of which abrogated normal seedling growth [134–137]. Interestingly, the phenotypes including the arrest of post-germinative development in the absence of exogenous sucrose and the root insensitivity to the auxin precursor indole-3-butyric acid could be rescued by OsACBP6 overexpression, indicating its participation in peroxisomal β-oxidation [38]. The CTSfacilitated peroxisomal import of precursors such as α-linolenic acid and 12-oxo-phytodienoic acid (or their CoA-esters) may also be crucial for jasmonate biosynthesis via a β-oxidative pathway [138]. Accordingly, the demonstrated binding of linolenoyl-CoA ester to rOsACBP6 may account for the restoration of wound-inducible jasmonate production in the cts mutant by OsACBP6 overexpression [38]. 4.2. Very-long-chain acyl-CoA esters Whilst bovine L-ACBP does not bind acyl-CoA esters with longer than 22 carbon atoms [33,42], the preference of some rAtACBPs for VLC acyl-CoA esters implicates plant-specific functions [74,82]. In transgenic Arabidopsis stems, the AtACBP1 promoter drove strong βglucuronidase (GUS) expression in the epidermis, which is a major site of VLC acyl-CoA synthesis for cuticle formation [139,140]. Given its high affinity to oleoyl-CoA and VLC acyl-CoA esters, AtACBP1 may facilitate channeling of these substrates for chain extension catalyzed by the ER-localized acyl-CoA elongase [74]. Thus, it is conceivable that depletion of AtACBP1 in the stem epidermis affects the biosynthesis of cuticular wax [74], which is derived from VLC acyl-CoA esters via the acyl reduction and decarbonylation pathways [141,142]. In atacbp1 mutant stems, the composition of cuticular waxes and cutin monomers was

7

altered in conjunction with down-regulated expression of wax and cutin biosynthetic genes, corroborating with the electron microscopic observations of unusual surface wax crystals and cuticle membranes (Table 2) [74]. In addition, the leaf wax content was reduced in atacbp1, rendering it more susceptible to B. cinerea infection [74]. In another study, the single mutants of atacbp3, atacbp4 and atacbp6 also exhibited higher susceptibility to pathogens including P. syringae and, occasionally, B. cinerea and C. higginsianum, owing to a defect in the generation of systemic acquired resistance (SAR) signals [89]. Compromised SAR induction was attributed to defective cuticles in these mutants which exhibited aberrant structures and composition in cuticular waxes and cutin monomers (Table 2) [89]. Resembling rAtACBP1, the binding of rAtACBP3 to VLC acyl-CoA esters was also reported [82]. As AtACBP3 is ER-targeted besides its apoplastic localization [47,80], it may share a similar role with AtACBP1 in the production of VLC acyl-CoA esters as precursors of cuticle constituents [74,89]. Apart from cuticle synthesis, the potential binding activity of AtACBP3 to VLC acyl-CoA esters at the ER has recently found relevance to the biogenesis of VLC-sphingolipids, possibly by controlling the incorporation of VLC acyl moieties into t18:0 sphinganine for the generation of ceramide and glycosyl inositol phosphorylceramide (GIPC) derivatives [82]. Consistently, the rosettes of AtACBP3-overexpressors exhibited lower VLC-GIPC content than the wild type upon submergence under light, in contrast with increased levels in AtACBP3-suppressors, more tolerant to submergence and ethanolic treatment [82]. On the other hand, AtACBP3-overexpressors were more sensitive to these stresses unless salicylic acid (SA) signaling was abrogated [82], in agreement with the role of VLCFAs and GIPC derivatives in triggering the SAmediated response [143]. A similar hypersensitive phenotype was observed upon depletion of the transcription factor (TF) MYB30 [82], which regulates stress-mediated VLCFA synthesis [144,145]. Consequently, the rescue of myb30 phenotypes by AtACBP3-RNAi pointed to a novel function of AtACBP3 in the hypoxic response by its regulation of VLCFA metabolism [82]. 4.3. Polyunsaturated acyl-CoA esters In addition to VLC acyl-CoA esters, rAtACBP3 binds arachidonyl-CoA ester for a potential role in the biotic stress response [78,79]. Similar to some other polyunsaturated FAs, arachidonic acid is a key mediator in plant-microbe interactions [146]. Although plants do not naturally contain arachidonic acid, it could be acquired during pathogen invasion [147]. In solanaceous plants, the recognition of arachidonic acid as a pathogen-secreted cue elicits programmed cell death, viral resistance and other defense responses [148–150]. In transgenic Arabidopsis, the engineered production of arachidonic acid and other eicosapolyenoic acids enhanced resistance to biotic challengers such as aphids, B. cinerea and an oomycete pathogen (Phytophthora capsici) but increased susceptibility to P. syringae, suggesting that these polyunsaturated FAs are mediators of biotic responses [151]. In accordance with the high affinity to arachidonyl-CoA ester, the apoplastic AtACBP3 may play a role in sensing pathogen attacks, which subsequently strengthens existing defense responses or triggers other signaling cascades [78]. By analogy with the endogenous production of eicosapolyenoic acids in transgenic Arabidopsis [151], down-regulation of AtACBP3 in the TDNA mutant or RNAi lines rendered Arabidopsis more tolerant to B. cinerea but less resistant to P. syringae infection, and vice versa for AtACBP3-overexpressors [78]. Bacterial disease resistance of AtACBP3overexpressors was further linked to the constitutive expression of pathogenesis-related genes dependent on the SA-mediated signaling pathway [78]. As arachidonic acid also induces AtACBP3 expression, the lipidation of AtACBP3 is considered to be part of the defense mechanism [78]. The affinities of rAtACBP1 and rAtACBP2 to linoleoyl-CoA and linolenoyl-CoA esters are pertinent to their role in the repair of membrane phospholipids after heavy metal-induced peroxidative damage

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

8

S.-C. Lung, M.-L. Chye / Biochimica et Biophysica Acta xxx (2016) xxx–xxx

[68,69,77]. In metal toxicity, the redox homeostasis of plants is perturbed due to the induced formation of free radicals and reactive oxygen species leading to lipid peroxidation and loss of membrane integrity [152]. As an adaptation, the peroxidized acyl moieties are cleaved from the membrane PC and the resulting lysoPC can be reacylated with native FAs by the forward reaction of LPCAT [153], which has a preference for unsaturated C18 (oleoyl-, linoleoyl- and linolenoyl-) acyl-CoA esters [154]. Thus, the binding activities of membrane-localized AtACBP1 and AtACBP2 to linoleoyl-CoA and linolenoyl-CoA esters are deemed favorable for this protective acyl exchange reaction [68,69,77], as the enhancement of LPCAT activity by Class I BnACBP has been demonstrated [59,60]. Consistently, transgenic Arabidopsis overexpressing AtACBP1 or AtACBP2 were more tolerant to lead (II) and cadmium (II), respectively [68,69,77]. The AtACBP2-overexpressors were also less sensitive to hydrogen peroxide and contained lower lipid hydroperoxide content upon cadmium (II) treatment than the wild type [68,69]. Not surprisingly, wild-type Arabidopsis roots were up-regulated in AtACBP1 and AtACBP2 expression on exposure to lead (II) in the medium in response to heavy metal stress [68,69,77]. 5. Association with phospholipids Aside from acyl-CoA esters, all Arabidopsis and rice ACBP isoforms appear to associate with at least one class of phospholipids as demonstrated by in vitro filter-binding assays (Table 1). In some studies, ACBP-phospholipid interactions were further supported by experiments such as Lipidex competition [69], lipid pull-down [71], protein-lipid overlay [75] and liposome-binding [80] assays, and measurement of their dissociation constants is needed to provide more precise parameters of their interaction. Regarding ligand specificities, plant ACBPs resemble LTPs which also bind phospholipids, lyso-derivatives and acyl-CoA esters, albeit with different affinities [155]. While the extracellular localization of LTPs rules out a possible intracellular significance [23,24,156], the widespread subcellular distribution of different AtACBPs highlights their importance in supporting functions of phospholipids that constitute both structural membranes and mobile signals. As a first example, AtACBP2 interacts with lysoPC besides acyl-CoA esters, all of which represent substrates for rebuilding structural membranes upon heavy metal-induced damage [68,69]. In this process, phospholipase A (PLA) hydrolyzes membrane PC into lysoPC and free FAs [157]. If lysoPC is not reacylated immediately, it serves as a stress signal [157], that conveys messages to the vacuole for eliciting phytoalexin biosynthesis [158]. Given the toxicity of lysoPC, its intracellular concentration is controlled via acylation and deacylation catalyzed by LPCAT and lysophospholipases (LYSOPLs), respectively [153,157]. Besides lysoPC, AtACBP2 associates with LYSOPL2 via protein–protein interaction at the plasma membrane [69]. Thus, cadmium tolerance in AtACBP2- or LYSOPL2-overexpressing Arabidopsis is correlated with a higher lysoPC detoxification rate [69]. Additionally, AtACBP2 may control the fate of lysoPC as a stress signal during cadmium-induced oxidative stress [69]. In fact, it is probable that the phospholipid affinities of plant ACBPs are stress-related as elucidated in other studies. For instance, cold tolerance is regulated by AtACBP1 and AtACBP6, both of which bind PC and the former also binds phosphatidic acid (PA) [51,63,75]. AtACBP6 expression is cold-inducible at transcript and protein levels, and the overexpression of AtACBP6 up-regulates PHOSPHOLIPASE Dδ (PLDδ) expression [51]. In rosettes of freezing-tolerant AtACBP6- or PLDδoverexpressors, the enhanced hydrolysis of PC during freezing may generate signaling PA to mitigate hydrogen peroxide-promoted physical damage and programmed cell death (Table 2) [51,159,160]. This PLDδderived PA may also inhibit the action of PLA and thus reduce the production of membrane-damaging lysophospholipids [160]. This proposed freezing-resistant mechanism is, however, organ-specific, as freezingtolerant flowers of AtACBP6-overexpressors accumulated more PC and

monogalactosyldiacylglycerol but less PA (Table 2) [63]. In rosettes of AtACBP1-overexpressors, an increase in PA at the expense of PC was attributed to the up-regulated expression of PLDα1 (Table 2) [75], and it was later suggested that AtACBP1 enhances its enzyme activity via protein–protein interaction [71]. Consistent with the freezing tolerance and sensitivity of PLDα1- [161] and PLDδ-deficient Arabidopsis [159], respectively, the overexpression of AtACBP1 and AtACBP6 led to reciprocal phenotypes [51,75]. Contrary to the beneficial effect of PLDδ-derived PA, the PLDα1-derived PA during freezing and post-stress recovery deteriorates membrane bilayer structures [160,161], which could be alleviated by depletion of PLDα1 or AtACBP1 in mutant plants [75,161]. Hence, PA-interaction of AtACBP1 may be linked to its role in maintaining a membrane-associated PA pool and regulating the expression of both phospholipases [75]. The PLDα1-dependent function of AtACBP1 in phospholipid metabolism is not limited to the freezing response but also hormonal control of seed germination and post-germinative growth [71]. AtACBP1 expression is ABA- and drought-inducible [71]. The overexpression of AtACBP1 also regulates PLDα1 expression in Arabidopsis seedlings [71]. Along with the PA- and PC-association of AtACBP1, its protein–protein interaction with PLDα1 at the plasma membrane promotes the generation of PLDα1-derived PA (Table 2) [71], which mediates ABA signaling by inhibiting the phosphatase activity of a negative regulator, ABSCISIC ACID INSENSITIVE1 (ABI1) [162]. Thus, the overexpression of AtACBP1 up-regulated ABA-responsive genes and rendered freshly-harvested seeds more dormant and after-ripened seeds more ABA-sensitive than the wild type, whilst reciprocal seed dormancy was observed in atacbp1 [71]. Its homolog, AtACBP2, is also involved in ABA signaling, and the overexpression of AtACBP2 conferred drought tolerance by promoting ABA-mediated stomatal closure [70]. Other than ABA signaling, AtACBP1 and AtACBP2 share an overlapping role in membrane phospholipid biogenesis during embryo development [73]. The depletion of these two membrane-associated proteins in a double mutant resulted in very early embryo abortion [73], which is more severe than the phenotypes of a triple mutant of the three cytosolic AtACBPs [61]. Lipid profiling of the atacbp1 siliques revealed higher accumulation of stearoyl-CoA ester and monogalactosyldiacylglycerol at the expense of most polyunsaturated species of phospholipids than the wild type (Table 2) [73]. In another study, rosettes of AtACBP2RNAi lines also exhibited acyl compositional changes particularly for phospholipids (Table 2) [98]. Together with the affinities of rAtACBP1 for PA [75], rAtACBP2 for lysoPC [69] and both proteins for PC [71,73], these endomembrane-localized members can potentially mediate acyl exchange between the acyl-CoA and phospholipid pools which is crucial for membrane biogenesis during embryo development [73,163]. AtACBP3 is the sole isoform which interacts with PE, probably via its ACB domain as deletion of this domain disrupted this dissociation [80]. The PE-interaction of AtACBP3 is linked to its regulatory function during leaf senescence [80,83], in which autophagy contributes to the remobilization of intracellular constituents [164]. This turnover process features the sequestration of cytoplasm and organelles into autophagic vesicles which are directed to vacuolar hydrolysis [165]. The formation and trafficking of these vesicles are in part mediated by dual protein conjugation systems that couple AUTOPHAGY-RELATED8 (ATG8) and ATG12 to PE and ATG5, respectively [166,167]. ATG8-PE conjugation is reversible and facilitated by the ATG12-ATG5 complex, and is a major factor in autophagosome expansion [166]. The ATG8 lipidation is also controlled by AtACBP3 due to its competition for the same PE ligand [80]. The higher accumulation of PE in rosettes of AtACBP3-overexpressors promoted ATG8 degradation and disrupted autophagosome formation [80]. Accordingly, AtACBP3-overexpressors exhibited premature senescing phenotypes resembling other autophagy-defective mutants, indicating that the AtACBP3-mediated regulation of cellular lipid metabolism plays a role in starvation-induced and age-dependent leaf senescence [80,83].

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

S.-C. Lung, M.-L. Chye / Biochimica et Biophysica Acta xxx (2016) xxx–xxx

9

them, RELATED TO APETALA2.3 (RAP2.3) and RAP2.12 are group VII members of the ethylene response factor (ERF) family [173]. Interestingly, RAP2.3 forms complexes with multiple AtACBPs at distinct subcellular locations via different protein domains [67,88]. RAP2.3 interacts with the ankyrin-repeat domain of AtACBP2 at the plasma membrane [67], but it associates with AtACBP4 in the cytosol [88], possibly via its kelch motif [174]. The interaction with RAP2.3 may account for the immunolocalization of cytosolic AtACBP4 at the nuclear periphery [88]. Provided that the expression of both AtACBP4 and RAP2.3 was induced by B. cinerea infection or treatment with the ethylene precursor (1-aminocyclopropane-1-carboxylic acid) or methyl jasmonate, AtACBP4–RAP2.3 interaction seems related to ethylene- and/or jasmonate-mediated defense responses [88]. Whilst the physiological relevance of AtACBP2–RAP2.3 interaction has not been demonstrated, the protein complexes of RAP2.12 with AtACBP1 and AtACBP2 at the plasma membrane were linked to oxygen sensing and hypoxic responses [76]. Under aerobic conditions, RAP2.12 is kept away from the nucleus and protected from proteasomal degradation by protein–protein interaction with plasma membrane-bound AtACBP1 and AtACBP2 [76]. During flooding, RAP2.12 is released into the nucleus for promoting gene expression for hypoxia acclimation [76]. Upon reoxygenation, RAP2.12 is targeted by the ubiquitin-dependent N-end rule pathway for protein degradation [76], resembling other group VII ERFs [175]. AtACBP1 also binds another TF, ABA-RESPONSIVE ELEMEMT BINDING PROTEIN1 (AREB1) [176], of which the expression was upregulated to a greater extent in AtACBP1-overexpressors than the wild type in response to ABA [71]. Given that AREB1 is a transcription activator of ABA-inducible genes [177], it would be interesting to further elucidate its relationship with AtACBP1 in the future.

6. Heavy metal binding The affinity of ACBPs for heavy metals was first discovered in lead (II)-exposed human kidney [168]. Yet, the highly homologous 10-kDa equivalent rAtACBP6 did not bind lead (II) in vitro [68,77]. Instead, the lead (II)-binding capability was exhibited by larger isoforms including Arabidopsis rAtACBP1, rAtACBP2 and rAtACBP4, whilst rAtACBP2 also binds cadmium (II) and copper (II) [68,77,169]. Consistently, amongst the six AtACBP genes, only AtACBP1, AtACBP2 and AtACBP4 were lead (II)-inducible in both shoot and root tissues [77,169]. In transgenic Arabidopsis, the overexpression of AtACBP1 and AtACBP2 promoted tolerance to lead (II) and cadmium (II), respectively, which was associated with polyunsaturated acyl-CoA and phospholipid metabolism as discussed in the previous sections [68,69,77]. Further, the role of AtACBP2 in heavy metal binding was reinforced via its protein–protein interaction with FARNESYLATED PROTEIN6 (AtFP6), which has an M/ LXCXXC motif for binding lead (II), cadmium (II) and copper (II) [68]. Thus, the similar metal-binding properties of these two interacting proteins implicate a collaborative role in heavy metal transport in Arabidopsis roots [68]. More intriguingly, transgenic Brassica juncea plants overexpressing AtACBP1 or AtACBP4 were protected from lipid peroxidation in the presence of lead (II) due to its sequestration in the cytosol of root tips and vascular tissues, implicating the potential of metal-binding AtACBPs in phytoremediation [169]. 7. Protein–protein interacting partners In addition to lipidic ligands and heavy metals, ACBPs bind a number of protein partners that cooperate in metal-binding, and lipid metabolism or signaling [170], which were revealed in yeast two-hybrid screens and additional techniques such as bimolecular fluorescence complementation, fluorescence resonance energy transfer, co-immunoprecipitation and in vitro pull-down assays (Table 3). Amongst the identified protein partners, the majority are targets of Class II AtACBPs which possess an ankyrin-repeat domain for protein–protein interactions (Table 3). As reviewed in the previous sections, AtACBP2 interacts with AtFP6 and LYSOPL2 to confer heavy metal tolerance [68,69], whereas AtACBP1– PLDα1 interaction promoted ABA signaling and freezing tolerance [71, 75]. In a split-ubiquitin membrane yeast two-hybrid study, two isoforms of diacylglycerol transferases (VfDGAT1 and VfDGAT2) were identified as protein partners of VfACBP3A and VfACBP3B [171], pursuant to the observed stimulation of BnDGAT and AtDGAT activities by rBnACBP in vitro [6,7]. As VfDGAT1 and VfDGAT2 were localized to different ER subdomains and showed distinction in their affinity for eleostearic acidcontaining substrates [172], their complexes with VfACBP3A and VfACBP3B may play nonredundant roles in tung oil biosynthesis [171]. Other than metal-binding protein and lipid metabolic enzymes, AtACBPs interact with several stress-responsive TFs (Table 3). Amongst

8. Conclusions and perspectives Despite the functional conservation of all ACBPs in binding longchain acyl-CoA esters, more specific roles of plant ACBPs are discernible from their association with disparate ligands of acyl-CoA esters, phospholipids, heavy metals and protein partners. In the Plant Kingdom, the evolution of four classes of ACBPs added another level of complexity toward the characterization of their binding properties and implication of their functions. Over the past two decades, the resolved NMR and Xray structures of non-plant ACBPs have continued to provide mechanistic insights into their precise modes of protein-lipid interactions and probable explanations for the acyl-CoA selectivity of certain isoforms in relation to species-specific functions. In the future, the first plant ACBP structure will allow for a better understanding of its ligand versatility in contrast with non-plant homologs from a structural perspective. More ideally, structural studies of representative members from each of the four classes of plant ACBPs will further delineate their structure– function relationships and rationalize their differences in ligand specificities. In other approaches, reverse genetics and transgenic technology

Table 3 Protein–protein interacting partners of plant ACBPs. Protein category

Binding protein Enzyme

Transcription factor

Protein name

Interacting ACBP (Class)

Technique(s) used Y2H

BiFC

FRET

Pull-down

Co-IP

AtFP6 LYSOPL2 PLDα1

AtACBP2 (II) AtACBP2 (II) AtACBP1 (II)

+ + +

− − +

+ + −

+ − −

− + −

DGAT1, DGAT2 RAP2.12 EBP (RAP2.3)

VfACBP3A (III), VfACBP3B (III) AtACBP1 (I), AtACBP2 (II) AtACBP2 (II) AtACBP4 (IV) AtACBP1 (II)

+ + + + +

− + − − −

− − − + −

− − + − −

− − − + −

AREB1

Function

References

Heavy metal stress response Cadmium-induced oxidative stress response Abscisic acid signaling; Freezing tolerance N.D. Hypoxic stress response N.D. Defense response N.D.

[68] [69] [71,75] [171] [76] [67] [88] [176]

AREB1, ABSCISIC ACID-RESPONSIVE ELEMENT BINDING PROTEIN1; BiFC, bimolecular fluorescence complementation; Co-IP, co-immunoprecipitation; DGAT, DIACYLGLYCEROL ACYLTRANSFERASE; EBP, ETHYLENE-RESPONSIVE ELEMENT BINDING PROTEIN; FP6, FARNESYLATED PROTEIN6; FRET, fluorescence resonance energy transfer; LYSOPL2, LYSOPHOSPHOLIPASE2; N.D., not determined; PLDα1, PHOSPHOLIPASE Dα1; RAP, RELATED TO APETALA; Y2H, yeast 2-hybrid.

Please cite this article as: S.-C. Lung, M.-L. Chye, The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/j.bbalip.2015.12.018

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in conjunction with cell and molecular biological techniques, lipidomics and biochemical methods aided in the discovery of novel roles of AtACBPs in plant development and stress responses. Although ACBPrelated studies have been extended beyond the dicot model Arabidopsis to economically valuable crops such as oilseed rape, grape and tung tree, similar investigation in a monocot is still in its infancy. To this end, recent fundamental characterization of the rice ACBP family has laid a solid foundation for functional studies in the future [37,38]. Provided the conservation of protein interacting domains amongst plant ACBPs, protein interactome analysis remains one of the encouraging strategies to discover novel functions. Considering that AtACBPs play important roles in biotic and abiotic stresses, the examination of functional equivalents in commercial crops will identify promising candidates to improve agricultural productivity under adversity. Transparency document The transparency document associated with this article can be found, in online version. Acknowledgments MLC is grateful to the Wilson and Amelia Wong Endowment Fund, the Research Grants Council of the Hong Kong Special Administrative Region, China (HKU765813M), Hong Kong University Grants Committee (AoE/ M-05/12 and CUHK2/CRF/11G), and CRCG awards (104003169 and 104003561) from the University of Hong Kong (HKU) for supporting her work on plant ACBPs. SCL is supported by a HKU postdoctoral fellowship and CRCG award (Small Project Funding #201309176052). References [1] P.A. Watkins, Fatty acid activation, Prog. Lipid Res. 36 (1997) 55–83. [2] M. Berger, M.F.G. Schmidt, Identification of acyl donors and acceptor proteins for fatty acid acylation in BHK cells infected with Semliki Forest virus, EMBO J. 3 (1984) 713–719. [3] R. Lessire, H. Juguelin, P. Moreau, C. Cassagne, Elongation of acyl-CoAs by microsomes from etiolated leek seedlings, Phytochemistry 24 (1985) 1187–1192. [4] K. Waku, Origins and fates of fatty acyl-CoA esters, Biochim. Biophys. Acta 1124 (1992) 101–111. [5] A.P. Brown, P. Johnson, S. Rawsthorne, M.J. Hills, Expression and properties of acylCoA binding protein from Brassica napus, Plant Physiol. Biochem. 36 (1998) 629–635. [6] D.H. Hobbs, M.J. Hills, Expression and characterization of diacylglycerol acyltransferase from Arabidopsis thaliana in insect cell cultures, Biochem. Soc. Trans. 28 (2000) 687–689. [7] O.P. Yurchenko, R.J. Weselake, Involvement of low molecular mass soluble acyl-CoA-binding protein in seed oil biosynthesis, New Biotechnol. 28 (2011) 97–109. [8] B.S. Glick, J.E. Rothman, Possible role for fatty acyl-coenzyme A in intracellular protein transport, Nature 326 (1987) 309–312. [9] C.R. McMaster, Lipid metabolism and vesicle trafficking: More than just greasing the transport machinery, Biochem. Cell Biol. 79 (2001) 681–692. [10] D.M.F. van Aalten, C.C. DiRusso, J. Knudsen, The structural basis of acyl coenzyme A-dependent regulation of the transcription factor FadR, EMBO J. 20 (2001) 2041–2050. [11] A.D. Petrescu, R. Hertz, J. Bar-Tana, F. Schroeder, A.B. Kier, Ligand specificity and conformational dependence of the hepatic nuclear factor-4α (HNF-4α), J. Biol. Chem. 277 (2002) 23988–23999. [12] H.A. Hostetler, A.D. Petrescu, A.B. Kier, F. Schroeder, Peroxisome proliferatoractivated receptor α interacts with high affinity and is conformationally responsive to endogenous ligands, J. Biol. Chem. 280 (2005) 18667–18682. [13] M. Bronfman, M.N. Morales, A. Orellana, Diacylglycerol activation of protein kinase C is modulated by long-chain acyl-CoA, Biochem. Biophys. Res. Commun. 152 (1988) 987–992. [14] N.J. Faergeman, J. Knudsen, Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling, Biochem. J. 323 (1997) 1–12. [15] R.E. Gossett, A.A. Frolov, J.B. Roths, W.D. Behnke, A.B. Kier, F. Schroeder, Acyl-CoA binding proteins: multiplicity and function, Lipids 31 (1996) 895–918. [16] D. Neess, S. Bek, H. Engelsby, S.F. Gallego, N.J. Faergeman, Long-chain acyl-CoA esters in metabolism and signaling: role of acyl-CoA binding proteins, Prog. Lipid Res. 59 (2015) 1–25. [17] J. Knudsen, M.V. Jensen, J.K. Hansen, N.J. Faergeman, T.B.F. Neergaard, B. Gaigg, Role of acylCoA binding protein in acylCoA transport, metabolism and cell signaling, Mol. Cell. Biochem. 192 (1999) 95–103.

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