Glycosaminoglycans and Fibrillar Polymorphism

Chapter 26

Glycosaminoglycans and Fibrillar Polymorphism Kirsten G. Malmos and Daniel E. Otzen iNANO, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

Chapter Outline Introduction281 Proteoglycan Components Responsible for Protein Binding and Fibril Enhancement 282 The Polymeric Nature of GAGs is Important for Inducing Mature Amyloid Fibrils 283 GAGs Affect Fibril Morphology in Different Ways 283 Specificity of GAG–Protein Interactions 285

INTRODUCTION Components of amyloid deposits have been studied since the 19th century. In 1854 Virchow’s finding that deposits in the central nervous system contained cellulose-like polysaccharides connected the term amyloid to these deposits [1]. The amyloid name remained linked to the deposits even though Friedrich, in 1859, concluded that amyloid deposits consisted of protein [2]. Although these results were originally interpreted as contradictory, these two studies are the first evidence of co-localization of polysaccharides and proteins in amyloid deposits. In 1934 Meyer and co-workers used chemical component analysis to analyze glycosaminoglycans (GAGs) from connective tissue [3], enabling them to classify GAGs based on saccharide components and degree of sulfation [4–6]. Some 22 years later, they established that the polysaccharides of amyloid deposits in liver contained D-glucosamine and uronic acids with varying degree of sulfation [7]. They thereby linked the terms amyloid and glycosaminoglycans which, strictly speaking, both refer to the polysaccharide component of plaques. In 1965 the specificity of Alcian Blue towards GAGs was established [8], enabling visualization of GAGs in histologic preparations from amyloid-infected tissues. This technique has demonstrated that GAGs are a common feature of all amyloid deposits, irrespective of the protein component or the place of deposition [9–11]. Bio-nanoimaging. http://dx.doi.org/10.1016/B978-0-12-394431-3.00026-2 Copyright © 2014 Elsevier Inc. All rights reserved.

GAGs can Induce Fibrils in Non-Amyloidogenic Proteins 285 GAGs can Accelerate Fibrillation by Binding Monomers or by Interacting with Oligomers 285 Future Perspectives and Challenges: the Importance of Molecular Insights 288 Acknowledgments288

Proteoglycans (PGs) are proteins with one or more GAG chains attached. Membrane-bound PGs have been found to be involved in cell proliferation and cell signaling through binding of many growth factors. This binding occurs through the GAG chains and leads either to a direct activation or to an increase in the local concentration of growth factor and thereby, indirectly, to activation. Proteins bound to PGs are protected from proteolytic degradation [12]. Perlecan, a heparan sulfate-containing PG, is embedded in the basement membrane and contributes to its structure and function by providing negative charge in a non-symmetrical fashion [13]. The largest PG known (aggrecan) is a major structural component of connective tissue [12]. In this chapter we focus on the role of GAGs in fibrillation, inspired by their ubiquitous presence in all amyloid deposits. It is important to clarify whether GAGs interact unspecifically with proteins undergoing fibrillation, thereby getting trapped during the aggregation as ‘innocent bystanders’ unable to dissociate again, or whether they have an active role in the fibrillation process. As we elaborate below, this remains unclear. It has also been suggested that GAGs could serve to localize fibrils to specific anatomic compartments [14,15], that they could serve to protect fibrils from proteolytic degradation [16,17], and that they act as templates inducing stabilized oligomers, thereby

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promoting fibrillation [18–24]. To address these speculations, an understanding of the fibrillation process both in the presence and the absence of GAGs on a molecular level is needed. In the following we describe how GAGs in general can affect the fibril morphology of amyloidogenic proteins and also how GAGs can induce amyloid fibrils in proteins which do not normally fibrillate.

PROTEOGLYCAN COMPONENTS RESPONSIBLE FOR PROTEIN BINDING AND FIBRIL ENHANCEMENT In the extracellular matrix, most GAGs are bound to highly glycosylated PGs (Fig. 26.1), sometimes with other types of GAG linked to the same protein. This increases the heterogeneity of the already complex pool of GAGs, both in terms of composition and degree of sulfation, and makes it difficult to establish simple structure–activity relationships. Core proteins vary in size from 10 to 400 kDa and contain between one and fifteen GAGs linked through N or O-glycosidic linkages. The domains of core proteins are also very diverse: some contain membrane anchors, others contain both transmembrane and cytoplasmic domains, and yet others show no membrane association at all [25]. Although the core protein of heparan sulfate proteoglycan (HSPG) secreted from neuroblastoma cells itself binds to Aβ A4 monomers [26–28], there is no evidence that core

proteins enhance fibrillation. The consensus is that GAGs are responsible for inducing fibrillation [29–34]. The most abundant PGs contain primarily heparan sulfate (HS) GAG. HS is divided into regions of heparin structure and other regions with lower degrees of sulfation (Fig. 26.1). Figure 26.2A shows an example of a repeating disaccharide unit in a low-sulfated region of HS. Heparin is the GAG with the highest degree of sulfation, consisting of a repeating di-saccharide unit of iduronic acid and glucosamine linked only by 1-4 glycosidic linkages (Fig. 26.2B). Heparin’s biologic abundance and commercial availability makes it an obvious choice for initial screening for GAG effects on a given fibrillation process. Furthermore, heparin often shows the highest GAG amyloid-stimulating effect. The ranking heparin > heparan sulfate > chondroitin sulfate is observed for both Aβ and amylin [33–35]. This activity correlates with the degree of sulfation. As the degree of sulfation increases, so does amyloid fibril formation [33,34,36], indicating that the important interactions are ionic in nature. This is supported by the fact that fibrillation in the presence of GAGs is greatly affected by pH and ionic strength [30] and that PGs are displaced from Aβ at high salt concentrations [26]. The copious amount of GAGrelated protein fibrillation data recorded under various conditions has been systematically analyzed by single and multivariate analysis [37], which supported the correlation between sulfate content of the GAG and fibril enhancement, and verified that a high molarity of the solution can abolish the GAG effect.

FIGURE 26.1  Schematic representation of a hypothetical proteoglycan containing four common glycosaminoglycans: dermatan sulfate, chondroitin sulfate, heparin and heparan sulfate. These glycoaminoglycans are linked to serine by O-glycosidic linkages and through the typical xylose-galactose–galactose glycoside anchor. The sugar moieties are represented as shapes with varying color, and sulfate groups are shown as red dots. For heparan sulfate, the regional distribution of sulfate groups is marked by S for sulfated regions and A for acidic. Reproduced with permission from Imberty et al [64].

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FIGURE 26.2 The sugar components of heparin and heparan sulfate. (A) The disaccharide units of heparan sulfate consist of either a β-D-glucuronic acid pyranose or α-L iduronic acid pyranose with possible sulfate at O2. These are linked to α-D-N-acetylglucosamine in a 1-4 glycosidic linkage. The glycosamine can have sulfate groups at O6 or N. (B) The triple-sulfated disaccharide unit of heparin is highly consistent and represents 80–90% of the whole polymer structure. From left: the first sugar moiety is an α-L-iduronic acid pyranose unit linked in a 1-4 glycosidic link to an N-sulfated glucosamine with an additional sulfate group at O6. Reproduced with permission from Laremore et al [65].

THE POLYMERIC NATURE OF GAGs IS IMPORTANT FOR INDUCING MATURE AMYLOID FIBRILS The fact that free sulfate ions do not induce fibril formation in general (though they may have specific effects in some cases, e.g. against glucagon [38], indicates that the effect is promoted by the polymeric nature of GAGs. Work with other poly-anionic biomolecules, such as polyglutamate (poly-Glu) or RNA, indicates that poly-anions in general may affect fibrillation. Note, however, that poly-Glu stimulates protein fibrillation for some proteins [24,35,39] but not others [31]. This indicates that the structure of the polymer subunits is of variable importance. The degree of polymerization will also affect how well GAGs can stimulate fibrillation. Disaccharides of heparin can displace high-molecular-weight (HMW) heparin from Aβ-peptide [17], but are insufficient to mimic the effect of HMW heparin in immunoglobulin light chain, p25α and human muscle acylphosphatase (Fig. 26.3)[19,24,40]. Thus the minimum length required to induce fibrillation varies from disaccharide units for Aβ36, over tetrasaccharide units for gelsolin [41] to 10–14 saccharide units for p25α [24]. It is reasonable to imagine that for some proteins the polymeric nature of GAGs enables them to act as a templates, arranging monomers in protofibrils or oligomers as has been proposed for mAcP [22] and p25α [24]. Disaccharide units do bind protein [17], but they lack the ability to assemble protein monomers in an ordered manner. More kinetic data in other GAG-assisted fibrillation systems will show whether this is a general trend. Even though monosaccharides do not adequately reproduce the effects of HMW heparin, they can still affect fibril formation. Di-sulfated monosaccharides inhibit lateral aggregation

FIGURE 26.3 Fibrillation of 10 μg/mL p25α followed by thioflavin T fluorescence in the presence of depolymerized heparin of varying lengths: DP2 two saccharide units, DP6 six saccharide units, DP10 and DP14 ten and fourteen saccharide units. DP10 and DP14 traces resemble high-molecular-weight heparin. Adapted with permission from Nielsen et al [24].

of Aβ fibrils induced by HSPG, leading to the formation of protofibrils, suggesting sulfated monosaccharides as a therapeutic strategy against amyloidosis [36].

GAGs AFFECT FIBRIL MORPHOLOGY IN DIFFERENT WAYS HSPGs can also induce a change in fibril morphology [32,33,42], but this does not follow a simple pattern. In some systems, decreased lateral aggregation has been observed, whereas for other proteins, lateral aggregation was found to increase. Fibrils of α-synuclein formed without heparin are straight fibrils with diameters ranging from 6 to 12 nm, whereas GAGs make the fibrils thinner (6 nm diameter) and

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more curved, indicating that GAGs interfere with lateral aggregation of α-synuclein fibrils (Fig. 26.4). Decreased lateral aggregation of fibrils when incubated with GAG was also found for gelsolin [41]. For Aβ fibrils, the picture is completely the opposite. Fibrils from Aβ alone are long and thin. When Aβ is incubated with dermatan sulfate, the fibrils are thicker and contain a periodic twist (Fig. 26.5) [36]. Increased lateral aggregation was also induced when preformed fibrils were incubated with dermatan sulfate and heparin [42]. X-ray diffraction data have indicated that sulfate ions are found at regularly spaced positions along the fibril axis [29]. Antibody binding experiments suggest that GAGs are embedded in fibrils, making them inaccessible to GAG-specific antibodies [43]. This is consistent with solid-state NMR studies [44], suggesting that GAGs are embedded in mature fibrils. If GAGs are not only colocalized but incorporated into fibrils, it is reasonable that

it can affect their morphology. More surprising is the fact that not all fibrils change morphology when interacting with GAGs. However, there may be subtle undetected changes which are not visualized by the imaging techniques used. Not surprisingly, GAG binding also increases fibril stability. Fibrils of β2-microglobulin formed at low pH and in the presence of GAG were more stable against dilution than fibrils formed without GAGs (Fig. 26.6) [18]. Aβ1-42 fibrils showed the same trend when formed in the presence of the HSPG perlecan [32]. It has been suggested that fibrils containing GAGs are more stable towards enzymatic degradation [35,45,46]; however, no experimental evidence confirms this. Such an improved stability towards proteolysis could be either a consequence of changed morphology, e.g. denser packing of protofibrils, or simple steric blocking by binding, as seen with the protection of growth factor proteins by GAGs [12].

FIGURE 26.4  EM images of (A) α-synuclein fibrils formed alone, and (B) fibrils of α-synuclein formed in the presence of 75 μg/mL heparin. Fibrils induced with heparin appear thinner and are able to curve. Panels are approximately 500 nm wide. Reproduced with permission from Cohlberg et al [35].

FIGURE 26.5  (A) Negative stain EM images of Aβ Arg5His6→Ala aggregates. (B) Aggregates formed when protein is incubated with heparin. (C) protein incubated with chondroitin-4-sulfate. Aβ fibrils show increased lateral aggregation when incubated with GAGs. Scale bar represents 50 nm. Adapted with permission from McLaurin and Fraser [42].

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FIGURE 26.7  The anti-thrombin III binding pentasaccharide with the additional 3-O sulfate group (circled in red) in the central glucosamine. Reproduced with permission from Laremore et al [65].

FIGURE 26.6  Fibrils of β2-microglobulin formed at pH 2.5 in the presence of three different GAGs depolymerize at different rates when diluted into neutral (pH 7.4) buffer. The depolymerization is followed by a thioflavin T signal change over time from which depolymerization rates are obtained. The three GAGs stabilize fibrils in the ranking order heparin > chondroitin-6-sulfate > hyaluronic acid. Adapted with permission from Borysik et al [18].

SPECIFICITY OF GAG–PROTEIN INTERACTIONS Despite the large number of studies reporting binding of GAG to fibrillating proteins, it remains controversial whether the interaction is specific or not. Specificity is suggested to result from sulfation patterns or conformation of saccharide units [47,48] whereas long-range electrostatic interactions result in unspecific interactions [49,50]. Proposed consensus sequences for GAG binding are stretches of basic amino acids [51], with His residues responsible for the strong pH dependence of binding. Thus, a pentapeptide corresponding to residues 13–17 of Aβ, where His13 and His14 have both been replaced with Ser, does not bind to heparin, unlike the wild-type pentapeptide [30]. Basic amino acids have also been found to be important in heparin binding to Apo-serum amyloid A protein [52] and human muscle acyl phosphatase [22]. Combined mutation of all basic amino acids in Aβ1−28 to remove all basic side-chain groups clearly reduced GAG affinity but did not completely remove it, indicating that the basic amino acids are not the only binding groups in Aβ1−28 [42]. Specificity in GAG protein interactions could also be encoded in the GAG sequence and chemical structure. A minimal pentasaccharide containing an extra sulfate group at 3-O, which is not normally sulfated (Fig. 26.7), was established to constitute the anti-thrombin III-binding domain of heparin [47,53–55]. As GAGs are known to be heterogeneous polymers, it is possible that other special saccharide sequences induce specificity for a protein counterpart. To identify such sequences, better characterization methods for GAG components are needed. Unfortunately, the limited availability of biologically extracted GAGs currently impedes more detailed studies of these structures. L-Iduronic acid, found in heparin and heparan sulfate, can assume three different conformations: two chair forms, 1C and 4C (Fig. 26.2), and the less prevalent skewed boat 4 1

form 2S0. These conformations are accessible under physiologic conditions, inducing flexibility in the GAG polymer. This conformational freedom has been proposed to play a role in protein binding and fibril promotion [56], but the correlation was statistically shown to be insignificant [37].

GAGs CAN INDUCE FIBRILS IN NON-AMYLOIDOGENIC PROTEINS Most proteins do not form amyloid under physiologic conditions, but several of these otherwise non-amyloidogenic proteins can be induced by GAGs to fibrillate. Recently it has been found that many protein hormones can form fibrils when co-incubated with heparin [57]. Different granular vesicles containing hormones stain positive for amyloid structure [57], and heparin is also known to be stored in granular vesicles after synthesis [58]. Combining these observations, it has been suggested that heparin and hormone peptides are packed together in granular vesicles as a storage state prior to export [57]. In this case, heparin could act as a necessary component for fibril formation, being packed into vesicles along with peptide either because of specific interactions between the two or due to specific transport. Either scenario would lead to vesicles containing high concentrations of peptide and heparin at a slightly acidic pH (5.5), conditions favoring amyloid fibril formation [18,19,30]. Secretion leads to an increase in pH and dilution of heparin and peptides, which, in combination, may trigger the release of monomer peptides from the fibril reservoir, although this remains to be experimentally verified. This may be yet another example of the beneficial use of amyloid to self-assemble monomers into an active conformation. Functional amyloid is now known to occur in Nature across all species; amyloid fibrils are particularly widespread in bacteria, where they appear to play important structural roles in stabilizing intermolecular contacts for biofilm formation and possibly adhesion to eukaryotic cells [59].

GAGs CAN ACCELERATE FIBRILLATION BY BINDING MONOMERS OR BY INTERACTING WITH OLIGOMERS The ability of GAGs to induce amyloid fibrils in non-­ amyloidogenic proteins suggests that GAGs interact with protein at an early stage in the aggregation pathway. Several studies address how GAGs affect protein structure prior to aggregation. Circular dichroism (CD) spectra indicate that

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some proteins (e.g. mAcP, Tau, Aβ, α-synuclein) undergo an increase in β-sheet structure at the expense of random coil upon binding GAGs [22,23,42,60]. Such a structural rearrangement has not been observed for p25α, which maintains a native conformation upon binding to heparin [61]. Figure 26.8 shows CD spectra of Aβ monomers immediately after the addition of heparin or dermatan sulfate. The structural change that proteins such as Aβ, Tau and α-synuclein undergo in the monomeric state upon GAG addition suggests that the species interact at an early stage prior to the formation of mature fibrils [16,22,23,60]. It is also possible that this rapid structural change rather reflects the formation of a soluble oligomer, as observed for mAcP [22]. An early interaction of heparin and protein is also

indicated by the change in aggregation kinetics upon addition of GAGs. GAG addition tends to reduce fibrillation lag times in a dose-dependent manner [22,62]. Indeed, GAGs have been found to interact with monomers of both Aβ26,28, p25α [24], Tau [23] and mAcP [22,40,63], with the latter quickly forming oligomers. For the latter three proteins, systematic studies have enabled the proposal of different mechanisms of action. Common for these models is the binding event of protein monomers to GAG, with the major differences being binding stoichiometry, and whether monomer binding induces structural rearrangement of protein monomers. The protein mAcP has been used as a model for GAG-induced aggregation and has been the basis for a mechanism shown in Figure 26.9 [22].

FIGURE 26.8  Far UV CD spectra of (A) Aβ1-28 and (B) Aβ1-28 His13→Ala show that the peptides in all cases undergo changes in secondary structure upon addition of GAG. GAG is added to 1:1 (w/w). For both peptides, random coil structure dominate when no GAGs are present. Upon addition of GAGs the spectra indicate the presence of β-sheet structure. Reproduced with permission from McLaurin and Fraser [42].

FIGURE 26.9  Schematic model of muscle acylphosphatase (mAcP) aggregation induced by heparan sulfate (HS). Protein monomer absorb to HS, the resulting complex containing 14:1 mAcP to HS. These complexes then form β-sheet-rich oligomers in a second step. Adapted with permission from Motamedi-Shad et al [22].

Chapter | 26  Glycosaminoglycans and Fibrillar Polymorphism

mAcP aggregation consists of multiple phases, with the first being an ultrafast absorption of mAcP monomers to GAG polymers. The binding event is followed by a structural rearrangement forming oligomers rich in β-sheet structures and with thioflavin T-binding properties. These oligomeric species can be either on or off pathway, but the much slower elongation phase starts only after these initial phases have ended. In the same study, systematic mutagenesis showed that all basic residues contribute to binding affinity in some degree in an additive fashion. In contrast, only basic residues positioned in flexible loops near the N- and C-terminal seem to contribute to the GAG-accelerated aggregation. However, this model is not exhaustive. For one thing, the GAG:protein stoichiometric ratio ranges from 1:1 (Tau) [23] to 1:14 for mACP [22] and 1:25 for p25α [24]. The thioflavin T signal decreases; this is observed after the optimal GAG:protein ratio has been reached, and is explained differently for Tau and p25α. For Tau protein, saturation with GAG is suggested to leave excess GAGs in solution, increasing the

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solute molarity and thereby self-quenching the electrostatic interactions between GAG and protein [23]. For p25α we propose that extra GAG-binding sites are occupied above an optimum heparin concentration, enabling the protein to cross-bind heparin polymers and leading to amorphous aggregates with low thioflavin T-binding abilities [24]. Nevertheless, all models involve the GAG-induced acceleration of aggregation based on preferential binding to amyloid-precursor states. Schematic models of aggregation provide a visual understanding of the aggregation process, and when combined with a mathematical description to model experimental kinetic parameters, they possess predictive power which enables experimental verification of the model, as illustrated in Figure 26.10 [24]. Models of GAG action have also been proposed for transthyretin [21], gelsolin [20], and immunoglobulin light chain [19], in which GAGs do not interact with protein monomers but with oligomeric species, enhancing their assembly into fibrils. A schematic representation of

FIGURE 26.10  (A) Model and (B) fit of data for p25α aggregation. The model incorporates the observation that heparin binds in the molar stoichiometry 1 heparin : 25 p25α, at optimal aggregation, and that amorphous aggregates dominate at higher GAG concentrations. The concentration of p25α monomers decreases over time, but plateaus at approximately 3 μM for heparin concentrations 10 and 215 μg/mL. Adapted with permission from Nielsen et al [24].

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FIGURE 26.11  Schematic model of heparin-assisted gelsolin aggregation. In this model, heparin binds protein only after it has formed β-sheet-rich oligomers. Binding of oligomers then accelerates the fibrillation process. Adapted with permission from Solomon et al [20].

the proposed model for GAG-induced gelsolin aggregation is shown in Figure 26.11. For immunoglobulin light chains, GAGs were found not to interact with the resulting fibrils, but only with oligomeric species [19]. For gelsolin and transthyretin, the GAG chains are proposed to remain attached and incorporated into the mature fibrils [20,21].

FUTURE PERSPECTIVES AND CHALLENGES: THE IMPORTANCE OF MOLECULAR INSIGHTS It is now well-established that GAGs localize to amyloid deposits and accelerate the aggregation of many proteins, leading to faster formation of fibrils, sometimes with changed morphology. Nevertheless, many questions remain unanswered. As with all amyloid research, it is a challenge to construct general models for the formation of this distinctive structure when so many diverse proteins can undergo this transformation to GAG-supported amyloid. The proteins differ in sequence, structure, charge and (most likely) mode of interaction with GAGs, and the diversity of GAG molecules is also very high. Some protein monomers bind to GAG prior to fibrillation, and GAG remains associated also in the resulting fibrils, whereas for other proteins only oligomers transiently interact with GAGs. Nevertheless, general features have emerged, such as the importance of electrostatics. Investigating more proteins and resolving the molecular role of GAGs in their fibrillation process is of absolute importance to drive the field closer to a more general understanding of how simple electrostatic interactions can lead to complex and diverse effects. Another challenge is to obtain high-resolution structural information. In addition to elucidating which parts of the amyloid structure are preferred interaction sites for GAGs, it may also clarify why some GAGs promote lateral association while others do the reverse. We also need to understand how GAGs link to aggregate toxicity. It is unclear whether fibril acceleration is a beneficial effect. To clarify this, the molecular species and mechanisms leading to cytotoxicity have to be further addressed. Increased expertise in the isolation and analysis of oligomeric species will help us to answer this question.

ACKNOWLEDGMENTS We are grateful for support from the Danish Research Foundation (inSPIN) and Aarhus University.

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