Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I)

BBABIO-47568; No. of pages: 10; 4C: 3, 4 Biochimica et Biophysica Acta xxx (2015) xxx–xxx

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Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I)☆ Thorsten Friedrich a,b,⁎, Doris Kreuzer Dekovic a,b, Sabrina Burschel a a b

Albert-Ludwigs-Universität Freiburg, Institut für Biochemie, 79104 Freiburg i. Br., Germany Spemann Graduate School of Biology and Medicine, Albertstr. 19A, 79104 Freiburg i. Br., Germany

a r t i c l e

i n f o

Article history: Received 24 July 2015 Received in revised form 3 December 2015 Accepted 7 December 2015 Available online xxxx Keywords: Escherichia coli Complex I, NADH dehydrogenase NADH:ubiquinone oxidoreductase Assembly Iron–sulfur cluster

a b s t r a c t Energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, couples the electron transfer from NADH to ubiquinone with the translocation of four protons across the membrane. The Escherichia coli complex I is made up of 13 different subunits encoded by the so-called nuo-genes. The electron transfer is catalyzed by nine cofactors, a flavin mononucleotide and eight iron–sulfur (Fe/S)-clusters. The individual subunits and the cofactors have to be assembled together in a coordinated way to guarantee the biogenesis of the active holoenzyme. Only little is known about the assembly of the bacterial complex compared to the mitochondrial one. Due to the presence of so many Fe/S-clusters the assembly of complex I is intimately connected with the systems responsible for the biogenesis of these clusters. In addition, a few other proteins have been reported to be required for an effective assembly of the complex in other bacteria. The proposed role of known bacterial assembly factors is discussed and the information from other bacterial species is used in this review to draw an as complete as possible model of bacterial complex I assembly. In addition, the supramolecular organization of the complex in E. coli is briefly described. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Prof. Conrad Mullineaux. © 2015 Elsevier B.V. All rights reserved.

1. Introduction In cellular catabolism, energy is conserved as reducing equivalents such as NADH. The enzyme complexes of respiratory chains convert the energy of the reducing equivalents into an ion gradient across the membrane. This gradient is used in turn for energy-consuming processes such as ATP synthesis, active transport and motion. The energyconverting NADH:ubiquinone oxidoreductase, respiratory complex I, is the main entry point for electrons from NADH into the respiratory chains of most mitochondria and many bacteria [1–8]. Complex I links the transfer of two electrons from NADH to ubiquinone with the translocation of four protons across the membrane [9–12]. Its mechanism is not completely understood due to its enormous complexity. The bacterial complex I is generally made up of 14 individual subunits named NuoA to NuoN. In Escherichia coli they are encoded by the genes nuoA to nuoN [13] and represent the minimal structural set of subunits required for the activity of the complex [3,8]. As in a few other bacteria, the E. coli genes nuoC and nuoD are fused leading to the assembly of a complex consisting of 13 subunits [14]. Some bacteria such as Thermus thermophilus contain additional subunits that are not conserved within ☆ This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Prof. Conrad Mullineaux ⁎ Corresponding author at: 79104 Freiburg i. Br., Germany. E-mail address: [email protected] (T. Friedrich).

the complex I family [15,16,17]. The complex from and bovine heart is currently described as an assembly of 44 different subunits [18,19] and that of the yeast Yarrowia lipolytica of at least 42 [20]. These subunits include homologs of the 14 core subunits present in bacterial complex, seven are encoded by mitochondrial DNA in eukaryotes [1,2, 4,7,19,21]. 2. Structure and function of complex I X-ray crystallography [16,22] and electron microscopy [18,23,24,25] revealed that complex I is made up of a peripheral arm that is built up by the globular subunits NuoB, CD, E, F, G, and I, and a membrane arm containing the polytopic subunits NuoA, H, J, K, L, M, and N (Fig. 1). Accessory subunits of the mitochondrial complex are present in both arms [18,22,26]. The peripheral arm contains the redox groups of complex I, namely one flavin mononucleotide (FMN) and nine iron–sulfur (Fe/S)clusters, implicating its function in electron transfer. The homology of the three major subunits of the membrane arm NuoL, M, and N to monovalent cation/proton antiporters strongly suggests that this arm is involved in proton translocation. In recent years the understanding of the mechanism of complex I was largely expanded due to the success in obtaining structural information. The spatial arrangement of the cofactors became evident from the structure of the peripheral arm of T. thermophilus complex I solved at 3.3 Å resolution [15]. The structure of the membrane arm of the

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Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004

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T. Friedrich et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

Fig. 1. Schematic view of complex I. The peripheral arm is shown in light grey, the membrane in medium grey, and the horizontal helix (αH) and the β-hairpin helix structures (βH) of the membrane arm in dark grey. Q stands for ubiquinone, FMN for flavin mononucleotide, Nx for the Fe/Sclusters. The additional, non-conserved Fe/Scluster N7 of E. coli complex I is omitted from the figure for clarity. The approximate position of the substrate binding sites and the cofactors is given. The putative proton pathways consisting of two half-channels each and the ubiquinone binding side are shown in white. Amino acid residues comprising to the central hydrophilic axis within the membrane arm are shown as black dots.

E. coli complex at 3.0 Å revealed the presence of proton pathways [27]. The architecture of the entire T. thermophilus complex I was first described at 4.5 and later at 3.3 Å resolution [16,28]. The X-ray structure of the Y. lipolytica complex at about 3.8 Å resolution and the cryo-EM map of the bovine heart complex I at 5 Å contributed to the understanding of the ‘active’/’inactive’ transition of the mitochondrial complex and revealed the position of 14 out of the 31 accessory subunits [18,22,28]. From the structural data and biochemical studies the following picture of the mechanism of complex I emerged (Fig. 1). NADH donates a hydride to FMN, the primary electron acceptor of the complex, located at the peripheral arm. The two electrons are transferred via a chain of seven Fe/S-clusters to the ubiquinone-binding site [29]. The ubiquinone is directly reduced by the most distal cluster of the chain, N2. Another cluster that is not included in the chain and that in E. coli is temporarily reduced by NADH is located at the opposite side of the FMN [29]. Quinone reduction involves the participation of two quinone radicals [30, 31]. It is not yet clear how the energy released by the electron transfer in the peripheral arm is transmitted to the membrane arm to drive proton translocation. It is expected that the redox chemistry of the Fe/Scluster N2 and the reduction of the quinone are key processes for energy conversion [6–8,16,18,22]. The membrane arm of bacterial complex I is composed of seven subunits including the three subunits NuoL, M and N that derive from a common ancestor and that are homologues of monovalent cation/proton antiporters [16,22,32–35,36]. It was proposed that each antiportertype subunit provides a proton pathway consisting of two half-channels that are connected by a hydrophilic axis composed of charged and polar amino acid residues and located approximately in the middle of the membrane [16,22]. This hydrophilic axis traverses the membrane arm in its entire length (Fig. 1) connecting the ubiquinone reduction site with the three proton pathways mentioned above and the putative fourth proton pathway made up of NuoH, J and K [16,40]. It is proposed that proton pathways are functional in accordance with the proposed H+/e− stoichiometry of 2 [9–12]. The reduction of N2 and ubiquinone could lead to conformational changes that are transmitted to the membrane arm over a distance of approximately 180 Å by electrostatics. NuoL contains an additional C-terminal domain not present in NuoM and N, consisting of a 15th transmembraneous (TM) helix holding an unusual, 110 Å long amphipathic helix aligned parallel to the membrane arm and a 16th TM helix anchoring the ‘horizontal’ helix to the membrane arm. Such a ‘horizontal’ helix is also present in the

mitochondrial complex [18,22] and it is also conserved within the family of energy-converting hydrogenases and antiporters [28]. Recent studies showed that the helix most likely acts as a clamp stabilizing the membrane arm [37–39]. 3. Lessons learned from the modular evolution of complex I and mutagenesis of the nuo-operon While the assembly of the mitochondrial complex I from eukaryotes has been investigated in some detail [19,41,42], little is known about the assembly of the bacterial one. Phylogenetic analyses have shown that the bacterial complex evolved from preexisting modules for electron transfer and proton translocation [32–34]. The soluble NADH dehydrogenase module comprises the electron input part of the complex (Fig. 2). It is made up of the globular subunits NuoE, F, and G and harbors the FMN, the binuclear Fe/S-clusters N1a and N1b (nomenclature according to Ohnishi, for a different nomenclature, see [43]), and the tetranuclear Fe/S-clusters N3, N4, N5, and N7 [44–47]. The nonconserved cluster N7 on NuoG stabilizes the complex but it is not involved in electron transfer [46,47]. The NADH dehydrogenase module delivers the electrons from NADH to the amphipathic hydrogenase module, which is part of a family of multi-subunit membranous [NiFe] hydrogenases [48]. In complex I, this module is made up of the globular subunits NuoB, C, D, and I and of the polytopic subunits NuoH and one of the antiporter-type subunits. Structural data implicate that this subunit corresponds to NuoN (Fig. 2). It contains the tetranuclear clusters N2, N6a and N6b. The third module, the transporter module, transports protons across the membrane and contains subunits NuoL, M and K homologous to subunits of multi-subunit monovalent cation/proton antiporters [32–35]. It is reasonable to assume that assembly intermediates of the bacterial complex at least partly resemble these modules. An NADH dehydrogenase fragment consisting of the same subunits and cofactors as the NADH dehydrogenase module was biochemically obtained by splitting the preparation of the E. coli complex I with the lipid depleting detergent Triton X-100 [49]. However, this fragment was not assembled by overexpression of nuoEFG [44]. Only overexpressing nuoBCDEFG led to the production of the NADH dehydrogenase fragment in the cytoplasm. Furthermore, the dehydrogenase fragment was enriched in the cytoplasm of single nuo-deletion mutants lacking either nuoA, CD, H, I, J, K, M or N [50,51]. This indicates that the assembly of the NADH dehydrogenase fragment depends at least on the presence

Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004

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Fig. 2. Modular structure of complex I. The NADH dehydrogenase module is shown in light grey, the hydrogenase modul in medium grey and the transporter module in dark grey. The subunit composition and the cofactor content of every module are provided. Homologues of NuoA and J are not present in any of the modules.

of NuoB and needs the polytopic subunits to be anchored to the membrane. Further insights into a possible assembly route came from a bioinformatic analysis of available bacterial genomes. In a representative survey of about 1.000 bacterial genomes, all 14 genes encoding the subunits of complex I were present in approximately half of the bacteria [52]. In 86% of the genomes containing the nuogenes they are co-localized as nuoA to nuoN indicating that they are part of a polycistronic operon [52]. Gene nuoA encodes a polytopic membrane protein that might represent an anchor protein for further assembly of the complex at the membrane surface. The ribosome translating the nuo-mRNA is directed to the Sec-translocon by the SRP due to the presence of a signal anchor sequence in NuoA. This would tether the mRNA to the bacterial membrane and lead to a translation of nuoB to nuoI encoding globular proteins close to the membrane circumventing time-consuming diffusion processes and the use of additional chaperones. We propose that the ribosome stays at the membrane while synthesizing the globular subunits [53]. In addition, it was shown that cisacting sequences within the transmembrane-coding sequence of membrane proteins target mRNA to the membrane [54]. NuoA is involved in H-bonding with the globular NuoB possibly providing together with NuoCD a platform for the further assembly of the dehydrogenase fragment (Fig. 3). The further addition of NuoH translated from the polycistronic mRNA might tighten the interaction of the assembled peripheral arm by additional interactions to NuoB, CD and I. After strengthening the connection between the peripheral and the membrane arm by acquisition of NuoJ and K, the membrane arm

might be extended by another assembly intermediate consisting of the three major subunits NuoL, M and N. NuoL, located at the most distal position of the membrane arm, contains the horizontal helix that aligns parallel to the membrane arm bridging NuoL with NuoM, N and J. The deletion of nuoL does not disturb the assembly of the residual complex indicating that these three subunits might be attached to the residual complex en bloc. 4. Assembly factors of complex I The assembly of complex I containing up to ten Fe/S-clusters is as a matter of course tightly interconnected with the biogenesis of Fe/S-clusters. Several excellent reviews describe the biogenesis of Fe/S-clusters in mitochondria and bacteria [55,56]. Here, we will just give a brief introduction of that process and then describe the function of other assembly factors that are either also involved in the biogenesis of Fe/S-cluster or whose function is still under discussion. The abbreviations used in this chapter are summarized in Table 1. 4.1. The general Fe/S-cluster biogenesis systems There are two main Fe/S-cluster biosynthesis pathways in both prokaryotes and eukaryotes: the ISC (from: iron sulfur cluster) and SUF (from: sulfur formation) system [57–59]. The third known pathway, NIF (from: nitrogen fixation), is found in several bacteria catalyzing nitrogen fixation. On the contrary to the ISC and SUF that are generally

Fig. 3. Scheme of the proposed assembly pathway of bacterial complex I. The ribosome (not drawn in scale) is shown in blue; the mRNA is represented by the black line. The sequential addition of individual subunits is indicated by the letter of the respective E. coli complex I subunit.

Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004

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Table 1 Names of genes and proteins possibly involved in the maturation of E. coli complex I Gene

Protein

Full name

Putative function

cadA ravA, yieN viaA, yieD, yieM nfuA, gntY, yhgI cyaY

LdcI, CadA RavA ViaA NfuA CyaY

Lysine decarboxylase, inducible Regulatory ATPase variant A VWA domain protein interacting with AAA ATPase Fe/S biogenesis protein NfuA –

yajL, thiJ

YajL

Probable protein deglycase

Cellular pH stress regulation at mild acid stress (pH ~ 5) Metal insertion or chaperone activity Stimulator of RavA ATPase activity Scaffold/chaperone for damaged Fe/S-proteins Maturation of apo-proteins under normal and iron-rich conditions Protectant covalent chaperone activity with sulfenylated thiol proteins by forming mixed disulfides upon oxidative stress

used for the maturation of all Fe/S-proteins, the NIF system is used exclusively for the maturation of the different types of nitrogenases [60– 62]. In E. coli both, the ISC and SUF systems are present. The general mechanism of assembly and delivery of an Fe/S-cluster is very similar in both systems (Fig. 4). Sulfur is extracted from L-cysteine by a cysteine desulfurase (IscS/SufS). Iron and sulfur meet on the scaffold protein (IscU/SufB) on which the cluster is assembled. The cluster is released from the scaffold with the help of ATP-hydrolysing components (HscAB/SufBC2D) and transferred either directly or via A-type carriers (ATCs; IscA/SufA) to the individual apo-proteins (Fig. 4). The source of iron is still under debate. In eukaryotes, frataxin was proposed as the most likely candidate [63], however, the situation in bacteria is more complex. The E. coli frataxin homologue, CyaY, interacts with the cysteine desulfurase IscS as well as with the scaffold IscU, but its affinity to iron is low and a cyaY deletion does not show such a drastic loss of Fe/S-enzyme activities as in eukaryotes [64–66]. In addition, the deletion of cyaY has no effect on the assembly of the E. coli complex I [67]. The other candidate protein for iron delivery, IscA, has a high affinity for iron but it does not interact with the cysteine desulfurase nor with the scaffold proteins [68–70]. The ISC system is supposed to be the house-keeping system, while SUF is the system used under stress conditions [57]. The reason for this classification arises from the sensitivity of the ISC system to reactive oxygen species (ROS). The ISC system is inactivated by ROS and at the same time suf transcription is strongly increased [71–75]. Furthermore, the SUF system is found to be more suitable at iron and/or sulfur limiting conditions [76–79]. In order to assure a correct assembly and maturation of all Fe/S-cluster proteins at highly diverse growing conditions there are additional factors. Some of these additional factors are ErpA,

an alternative ATC [80], CsdAE, a potential alternative source of sulfur [81], Mrp, a potential scaffold protein [82], NfuA, a Fe/S-cluster carrier protein [83,84], and others. 4.2. NfuA The ‘non-ISC, non-SUF’ factors present in prokaryotes and eukaryotes are suggested to play a role in Fe/S-cluster assembly and delivery under oxidative stress and iron starvation [85,86]. One such factor, Nfu was identified in humans, Arabidopsis thaliana and bacteria [83,85,87, 88]. The characteristic Nfu domain contains a conserved Cys–X–X–Cys sequence motif. This motif was first identified in the C-terminal Nfulike domain of NifU from Azetobacter vinelandii that was demonstrated to be important for the Fe/S-cluster assembly [89–91]. It was reported that both bacterial and mitochondrial Nfu binds and transfers [4Fe–4S] clusters in vitro [85,87,88,92–94]. The E. coli NfuA consists of a C-terminal Nfu domain and an N-terminal ATC* domain. The asterisk indicates the presence of a ‘degenerated’ ATC domain that is not able to bind an Fe/S-cluster but is instead responsible for a more efficient interaction of NfuA with its apo-target. Both domains are required for the in vivo activity of NfuA [83,85,92,93]. NfuA interacts with both main Fe/S-cluster biogenesis pathways, ISC and SUF, by acting downstream of their respective scaffold proteins IscU/HscBA and SufBC2D (Fig. 4). NfuA receives a Fe/Scluster from the scaffolds and transfers it to the ATCs IscA and SufA, as well as to apo-protein directly [85,93,94]. Furthermore, transcriptomic studies revealed an enhanced expression of nfuA under cellular condition inducing protein misfolding in E. coli. Considering that NfuA was also found to be important for the viability of E. coli under oxidative

Fig. 4. A rough scheme of the assembly and insertion of Fe/S-cluster into individual apo-proteins. Red dots indicate the Fe-atoms and yellow dots the sulfur. Homologous proteins of the ISC- and the SUF-system are shown in the same color. The names of the proteins involved are explained in the text (modified from [56,57]).

Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004

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stress and iron starvation it was proposed that NfuA might act as a scaffold/chaperone for damaged Fe/S-proteins [83,95–97]. It was proposed that NfuA is involved in the maturation of complex I subunit NuoG by means of pull-down assays [94]. The complex I activity of the nfuA deletion strain was reduced by 40% at normal aerobic growth and by 60% at oxidative stress condition. The observed reduced activity was not due to a reduced level of complex I, instead it was postulated that in aerobic growth NfuA helps NuoG to acquire an Fe/S-cluster from the ISC system, while under oxidative stress the cluster is acquired from the SUF system. Interestingly, the mitochondrial homologue, Nfu1, was identified to be necessary for the efficient assembly of respiratory complexes I and II, which further strengthens the hypothesis that NfuA is an assembly factor of complex I [98]. 4.3. CyaY CyaY is the frataxin homologue of E. coli. The members of the highly conserved frataxin family are small acidic proteins known to bind iron with a low affinity and suggested to be involved in Fe/S-cluster biogenesis [99–107]. In humans frataxin-deficiency leads to a progressive neurodegenerative disease called Friedreich's ataxia [108–110]. Furthermore, it was reported that frataxin deficiency in humans and yeast results in the accumulation of mitochondrial iron, diminishes Fe/S-cluster protein activity, decreases heme synthesis and mediates hypersensitivity to oxidants [104,111–114]. Phylogenetic co-occurrence of frataxin-encoding genes and hscBA of the ISC system further strengthens the proposed involvement of frataxin in the Fe/S-cluster biogenesis [115]. So far, it is proposed that frataxin functions as an iron donor, an iron chaperone and as an iron sensing regulator of the ISC system [99,102,116–118]. The E. coli cyaY deletion mutant showed no significant phenotype [119]. The same was true for Salmonella enterica, where just a slight decrease in activity of Fe/S-cluster proteins and an enhanced sensitivity to H2O2 was observed [108–110,120–122]. It was reported that in E. coli CyaY is able to bind to the cysteine desulfurase IscS and the scaffold protein IscU and inhibit Fe/S-cluster formation on IscU in vitro [123–126]. Recent data suggests that bacterial CyaY also plays a role in the ISCmediated Fe/S cluster biogenesis in vivo, contributing to the maturation of apo-proteins under normal iron-rich conditions [127]. The possible involvement of CyaY in the assembly of E. coli complex I was investigated after the discovery of the additional fifteenth subunit, Nqo15, as structural component of the T. thermophilus complex [15, 128]. This novel subunit was identified as a frataxin homolog and shows a 2.5 Å RMSD to the structure of CyaY [15,67,129]. Nqo15 is encoded in a locus separated from the nqo-operon that encodes the fourteen core complex I genes in T. thermophilus. It is suggested that this subunit has a chaperone-like function and might stabilize the complex by eventually delivering iron to the Fe/S-clusters of the T. thermophilus complex I [128]. The deletion of cyaY in E. coli resulted in a decreased amount of complex I and complex II in the cytoplasmic membrane by approximately one third and one quarter, respectively. Complex I present in the cyaY deletion mutant was, however, fully assembled and contained all known cofactors. Furthermore, it was confirmed that CyaY is not a structural component of the E. coli complex I [67]. Based on these findings it was suggested that there is a transient interaction between CyaY and complex I, but that CyaY does not play an essential role in the assembly of complex I [67]. Since CyaY seems to play a role in the maturation of Fe/S-cluster containing proteins, as being part of the ISC-mediated Fe/ S-cluster biogenesis, the diminished production of complex I and complex II in the cyaY deficient strain may be explained by a disturbance of the Fe/ S-cluster assembly machinery. 4.4. YajL YajL is the most closely related E. coli homologue of Parkinsonismassociated protein DJ-1 and belongs to the DJ-1/Hsp31/PfpI superfamily that includes, besides DJ-1, peptidases and chaperones [130–132]. The

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members of this superfamily have in common a domain with a ‘nucleophilic elbow’ that contains a functionally important cysteine. This well conserved cysteine residue plays a crucial role in the oxidative stress resistance mediated by YajL and DJ-1 [133–135]. DJ-1 and YajL have a highly similar three-dimensional structure [136,137] suggesting a similar function. Even though the cellular and biochemical function of YajL is still under discussion, its role in the oxidative stress response has been widely studied [130,133,138]. It was reported that YajL protects bacteria against oxidative stress and oxidative-stress-induced protein aggregation on the one hand by upregulating the expression of several stress proteins [134], and through a chaperone-like function on the other hand [138]. Upon oxidative stress YajL acts as a covalent chaperone forming mixed disulfides with proteins of the thiol proteome, including Fe/S-proteins. Accordingly, NuoG that contains 4 Fe/S-clusters coordinated by 15 cysteine residues was identified as a covalent substrate of YajL [139]. Besides forming mixed disulfides with YajL, it was demonstrated that an artificial oxidoreductase activity of complex I in the yajL deletion mutant was reduced by 72% without a change in the cellular complex I level. Since the reduced complex I activity of the deletion mutant was efficiently rescued by overproducing YajL or DJ-1, it was suggested that YajL and DJ-1 play a role in protecting complex I against oxidative stress by preventing its aggregation or keeping NuoG in an assembly competent state during insertion of Fe/S-[139]. 4.5. LdcI/RavA/ViaA The E. coli cytoplasmic inducible lysine decarboxylase (LdcI or CadA) provides together with the lysine/cadaverine antiporter CadB protection against mild acid stress (pH ~ 5) [140–144]. It catalyzes the proton-dependent decarboxylation of L-lysine to cadaverine and CO2 that in turn increases the internal pH of the cell [140,145]. While carbon dioxide passively diffuses out of the cell, cadaverine is actively exchanged for fresh lysine by CadB [141]. The genes encoding LdcI and CadB are organized in cadBA operon [142]. In a position upstream of cadBA, cadC encodes the transcription activator of the operon [142, 146]. CadC activates the operon together with LysP, a lysine permease that directly detects lysine in the cell. In the absence of lysine, LysP inhibits CadC by complex formation. In the presence of lysine, the activity of LysP is repressed leading to the release of CadC and the consequent activation of transcription of the cadBA operon [146,147]. Furthermore, the operon cadBA is strongly induced by low pH, anaerobic conditions and an excess of lysine. It is repressed by the accumulation of cadaverine that binds and inhibits CadC [142–144,146–148]. LdcI forms a circular decamer of five dimers, unexpectedly containing the binding site for the stringent response regulator/alarmone ppGpp [140,149]. ppGpp allosterically inhibits LdcI activity under normal cellular conditions. At slightly acidic conditions such as a cytoplasmic pH of 4–5, however, LdcI converts lysine to cadaverine despite the fact that ppGpp is still bound to it [140,150]. Due to the interaction of LdcI with a partially assembled complex I, it is suggested that LdcI plays an additional cellular role either in the assembly of complex I or for the repair and insertion of its Fe/S-clusters [50]. The production of a complex I variant lacking NuoL resulted in the accumulation of two distinct populations of the variant. One population contained all known cofactors and exhibited NADH:decylubiquininone oxidoreductase but showed a decreased proton translocation activity. The other population is enzymatically inactive due to the lack of the most distal Fe/S-cluster N2, however, this population was unexpectedly associated with LdcI as identified by mass spectrometry [50]. Even though the cellular significance of the interaction between the ΔNuoL variant and LdcI is unclear, it is more than unlikely that LdcI bound to complex I is involved in acid stress regulation. This is supported by the fact that LdcI forms a large supramolecular structure [140, 150], while only substoichiometric amounts of LdcI are bound to the ΔNuoL variant. Considering that LdcI interacts also with RavA, a member of the MoxR family, which is reported to exhibit chaperone-like

Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004

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functions and to be involved in the maturation and activation of metalcontaining enzyme complexes, it was suggested that LdcI together with RavA might play a role in the insertion or the repair of Fe/S-cluster N2 of E. coli complex I [151–158]. A further suggestion is that LdcI binds to the partially assembled complex I and keeps it in an assembly competent state [50]. RavA (regulatory ATPase variant A) is a member of the MoxR AAA+ (ATPases associated with various cellular activities) protein family [152]. The AAA+ proteins are involved in a wide range of cellular processes, but they all share the common feature of using the energy from ATP hydrolysis to induce conformational changes [159,160]. Even though the biochemical function of the MoxR proteins is still unknown, the data obtained so far suggest a chaperone-like role in the assembly and the activation of distinct protein complexes [160,161]. Furthermore, it was demonstrated that the MoxR-related CoxD in Oligotropha carboxidovorans is directly involved in the biogenesis of the [CuSMoO2] cofactor of the CO dehydrogenase by assisting the stepwise introduction of sulfur and copper in the preformed [MoO3] center of the enzyme [158]. The genes encoding MoxR proteins are usually found in the close proximity of genes coding for proteins containing the Von Willebrand Factor Type A (VWA) domain. The VWA domain is involved in protein-protein interactions and contains a binding motif for divalent metal cations [162,163]. For some organisms the concurrence of the MoxR-related and VWA was already demonstrated [156,157,164]. The corresponding VWA protein of RavA is ViaA, and both ravA and viaA genes are encoded by the same operon [152]. The function of the RavA–ViaA complex in vivo is still unknown. It was suggested that they might have a similar function as metal-chelatases, to which MoxR proteins are closely related [160]. Metal-chelatases that contain both the AAA+ and VWA domain, are reported to play a role in metal insertion [165]. Furthermore, RavA interacts strongly with LdcI forming a cage-like structure, which is composed of two LdcI decamers held together by five RavA hexamers [152,166]. This interaction does not affect the activity of LdcI, but the RavA ATPase activity is significantly increased. The ATPase activity is further increased upon addition of ViaA, suggesting the formation of a ternary RavA-ViaA-LdcI complex. A possible function of such a complex might be the regulation of RavA activity under acid stress conditions [152]. It was also reported that the interaction of RavA with LdcI reduces the inhibition of LdcI by ppGpp both in vitro and in vivo, suggesting that the cellular response to acid stress is fine-tuned by both ppGpp and RavA [166]. It was proposed that RavA and ViaA physically interact with specific complex I subunits. The primary targets under aerobic conditions are NuoA and NuoF and NuoCD under anaerobic conditions. It seems that ViaA mediates this interaction, since the deletion of viaA significantly decreased the binding of RavA to the above-mentioned complex I subunits. Considering i) the proposed function of MoxR-related proteins to play a chaperone-like role in the assembly and/or activation of specific protein complexes, ii) the influence of a ravA-viaA deletion on the expression of genes involved in Fe/S-cluster biogenesis in vitro [167], and iii) the interaction of RavA with LdcI it is reasonable to assume that the RavA-ViaALdcI complex assist the insertion of Fe/S-cluster(s) into complex I. 5. Supramolecular organization of complex I Persistent assemblies of enzyme complexes that catalyze consecutive or correlated reactions are called supercomplexes. They are formed in order to enhance the activity and stability of enzymes involved or to reduce the production of noxious byproducts. Considering the efficiency and the overall turnover rates of the whole respiratory chain in eukaryotes, an assembly or higher order organization of the respiratory complexes in form of supercomplexes is conceivable, although there is some criticism to this concept from kinetic data [168,169]. Such supercomplexes containing NADH:ubiquinone oxidoreductase, ubiquinol:cytochrome c oxidoreductase (complex III) and cytochrome c oxidase (complex IV) were detected by BN-PAGE, transmission

electron microscopy and single particle cryo-electron microscopy [170, 171]. The supercomplexes I + III2 + IV1-4, III2 + IV1-4 and I1-2 + III2 appeared in a defined stoichiometry among several eukaryotic organisms promoting the so-called “solid state” model for many years [170,172– 179]. A number of physiological functions such as optimizing the rate of oxidative phosphorylation by substrate channelling were proposed for supercomplex formation. According to the model, the formation of supercomplexes brings the individual enzyme complexes closer together and shortens the shuttling distances for electron carriers to minimize the loss of electrons and, thus, the generation of ROS [180–182]. The influence of supramolecular assemblies and of a disturbed assembly in context with mitochondrial diseases and aging [183,184] will remain an important issue. There are excellent contributions on that topic in this special issue by A. Magalon, A. Melo and M. Leake. Examples for the formation of supercomplexes of respiratory complexes have been reported for species from all domains of life [185]. In the archaeal domain a persistent association of complexes III and IV as well as SoxABCD and SoxM supercomplexes were described in Sulfolobus acidocaldarius [186,187]. Concerning the domain of eubacteria, cytochrome bc::caa3 supercomplexes of various stoichiometries were isolated from different Bacillus species [188,189]. In Corynebacterium glutamaticum and Mycobacterium smegmatis the presence of a supercomplex comprising cytochrome bcc and cytochrome aa3 oxidase was demonstrated [190]. Furthermore, a fully functional I1 + III4 + IV4 supercomplex was isolated from Paraccocus denitrificans [191,192]. Moreover, III4 + IV4 and III4 + IV2 supercomplexes were detected in that organism. An association between bc1 complex and cytochrome cbb3 oxidase was described in Bradyrhizobium japonicum [193]. In E. coli an association of complex I and Ndh, the alternative NADH dehydrogenase, and a formate:oxygen oxidoreductase supercomplex containing the bo3, bd-I ubiquinol oxidases and the aerobic formate dehydrogenase was reported [194,195, see also the contribution of M. Teixeira and A. Melo to this issue]. In contrast to the mitochondrial complexes the bacterial and archaeal supercomplexes were only detected by in vitro methods. The main lines of evidence supporting the existence of supercomplexes are the co-migration of respiratory complexes on blue native electrophoresis and the co-purification by sucrose gradient centrifugation. Both procedures require a solubilization of the membrane protein complexes with specific detergents. Therefore, the significance of these data regarding the occurrence of supercomplexes as functional in vivo entities remains uncertain. To validate the organisation of respiratory complexes in vivo, pairs of fluorescent fusions of single-labelled enzyme complexes were analyzed by total internal reflection (TIRF) microscopy and fluorescence recovery after photo bleaching (FRAP). To avoid artefacts possibly caused by overexpression, the genes of the fluorescent proteins were fused to the chromosomal genes encoding one subunit of the corresponding respiratory complex [196]. Microscopic examination of these strains and statistic analysis of the data showed an uneven distribution of the enzyme complexes in large patches that consist only of one kind of complex [196,197]. The ubiquinone diffusion coefficient was two orders of magnitude larger than the diffusion coefficient of the membrane patches contradicting the substrate channeling function of supercomplexes [197]. Thus, it remains an open question whether the supercomplexes described in other organisms also exist in vivo in E. coli. Conflict of interest I declare that the authors have no conflict of interests. Thorsten Friedrich as corresponding author. Acknowledgements The work in the authors' laboratory was supported by the Deutsche Forschungsgemeinschaft (DFG) FOR 929 and the DeutschFranzösische Hochschule (DFH) CDFA 04-07. S.B. gratefully acknowledges

Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004

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support from the Studienstiftung des deutschen Volkes. We thank Prof. Dr. Hans-Georg Koch, Institute of Biochemistry and Molecular Biology, University Freiburg, for helpful discussions.

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Please cite this article as: T. Friedrich, et al., Assembly of the Escherichia coli NADH:ubiquinone oxidoreductase (respiratory complex I), Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbabio.2015.12.004