Abstract
This chapter describes computational approaches to study amyloid formation. The first part addresses identification of potential amyloidogenic regions in the amino acid sequences of proteins and peptides. Next, we discuss nucleation and aggregation sites in protein folding and misfolding. The last part describes up-to-date kinetic models of amyloid fibrils formation. Numerous studies show that protein misfolding is initiated by specific amino acid segments with high amyloid-forming propensity. The ability to identify and, ultimately, block such segments is very important. To this end, many prediction algorithms have been developed which vary greatly in their effectiveness. We compared the predictions for 30 proteins by using different methods and found that, at best, only 50 % of residues in amyloidogenic segments were predicted correctly. The best results were obtained by using the meta-servers that combine several independent approaches, and by the method PASTA2. Thus, correct prediction of amyloidogenic segments remains a difficult task. Additional data and new algorithms that are becoming available are expected to improve the accuracy of the prediction methods, particularly if they use 3D structural information on the target proteins. At the same time, our understanding of the kinetics of fibril formation is more advanced. The current kinetic models outlined in this chapter adequately describe the key features of amyloid nucleation and growth. However, the underlying structural details are less clear, not least because of the apparently different mechanisms of amyloid fibril formation which are discussed. Ultimately, the detailed understanding of the structural basis for amyloidogenesis should help develop rational therapies to block this pathogenic process.
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References
Ahmed AB, Kajava AV (2013) Breaking the amyloidogenicity code: methods to predict amyloids from amino acid sequence. FEBS Lett 587:1089–1095
Alberti S, Halfmann R, King O, Kapila A, Lindquist S (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137:146–158
Andersen CB, Yagi H, Manno M, Martorana V, Ban T, Christiansen G, Otzen DE, Goto Y, Rischel C (2009) Branching in amyloid fibril growth. Biophys J 96:1529–1536
Belli M, Ramazzotti M, Chiti F (2011) Prediction of amyloid aggregation in vivo. EMBO Rep 12:657–663
Bennett MJ, Choe S, Eisenberg D (1994) Domain swapping: entangling alliances between proteins. Proc Natl Acad Sci U S A 91:3127–3131
Bennett MJ, Schlunegger MP, Eisenberg D (1995) 3D domain swapping: a mechanism for oligomer assembly. Protein Sci 4:2455–2468
Benson MD (2003) The hereditary amyloidoses. Best Pract Res Clin Rheumatol 17:909–927
Bezsonov EE, Groenning M, Galzitskaya OV, Gorkovskii AA, Semisotnov GV, Selyakh IO, Ziganshin RH, Rekstina VV, Kudryashova IB, Kuznetsov SA, Kulaev IS, Kalebina TS (2013) Amyloidogenic peptides of yeast cell wall glucantransferase Bgl2p as a model for the investigation of its pH-dependent fibril formation. Prion 7:175–184
Binger KJ, Pham CLL, Wilson LM, Bailey MF, Lawrence LJ, Schuck P, Howlett GJ (2008) Apolipoprotein C-II amyloid fibrils assemble via a reversible pathway that includes fibril breaking and rejoining. J Mol Biol 376:1116–1129
Bucciantini M, Calloni G, Chiti F, Formigli L, Nosi D, Dobson CM, Stefani M (2004) Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem 279:31374–31382
Buxbaum JN, Linke RP (2012) A molecular history of the amyloidoses. J Mol Biol 421:142–159
Carrió M, González-Montalbán N, Vera A, Villaverde A, Ventura S (2005) Amyloid-like properties of bacterial inclusion bodies. J Mol Biol 347:1025–1037
Chamberlain AK, MacPhee CE, Zurdo J, Morozova-Roche LA, Hill HA, Dobson CM, Davis JJ (2000) Ultrastructural organization of amyloid fibrils by atomic force microscopy. Biophys J 79:3282–3293
Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366
Chiti F, Webster P, Taddei N, Clark A, Stefani M, Ramponi G, Dobson CM (1999) Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc Natl Acad Sci U S A 96:3590–3594
Chiti F, Taddei N, Baroni F, Capanni C, Stefani M, Ramponi G, Dobson CM (2002) Kinetic partitioning of protein folding and aggregation. Nat Struct Biol 9:137–143
Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM (2003) Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 424:805–808
Cohen SIA, Vendruscolo M, Welland ME, Dobson CM, Terentjev EM, Knowles TPJ (2011) Nucleated polymerization with secondary pathways. I. Time evolution of the principal moments. J Chem Phys 135:065105
Cohen SIA, Linse S, Luheshi LM, Hellstrand E, White DA, Rajah L, Otzen DE, Vendruscolo M, Dobson CM, Knowles TPJ (2013) Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A 110:9758–9763
Collins SR, Douglass A, Vale RD, Weissman JS (2004) Mechanism of prion propagation: amyloid growth occurs by monomer addition. PLoS Biol 2:e321
Das M, Mei X, Jayaraman S, Atkinson D, Gursky O (2014) Amyloidogenic mutations in human apolipoprotein A-I are not necessarily destabilizing – a common mechanism of apolipoprotein A-I misfolding in familial amyloidosis and atherosclerosis. FEBS J 281:2525–2542
De Groot NS, Castillo V, Graña-Montes R, Ventura S (2012) AGGRESCAN: method, application, and perspectives for drug design. Methods Mol Biol 819:199–220
Dobson CM (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24:329–332
Dovidchenko NV, Finkelstein AV, Galzitskaya OV (2014) How to determine the size of folding nuclei of protofibrils from the concentration dependence of the rate and lag-time of aggregation. I. Modeling the amyloid protofibril formation. J Phys Chem B 118:1189–1197
Emily M, Talvas A, Delamarche C (2013) MetAmyl: a METa-predictor for AMYLoid proteins. PLoS One 8:e79722
Esteras-Chopo A, Serrano L, López de la Paz M (2005) The amyloid stretch hypothesis: recruiting proteins toward the dark side. Proc Natl Acad Sci U S A 102:16672–16677
Fändrich M, Fletcher MA, Dobson CM (2001) Amyloid fibrils from muscle myoglobin. Nature 410:165–166
Fändrich M, Forge V, Buder K, Kittler M, Dobson CM, Diekmann S (2003) Myoglobin forms amyloid fibrils by association of unfolded polypeptide segments. Proc Natl Acad Sci U S A 100:15463–15468
Ferguson N, Berriman J, Petrovich M, Sharpe TD, Finch JT, Fersht AR (2003) Rapid amyloid fiber formation from the fast-folding WW domain FBP28. Proc Natl Acad Sci U S A 100:9814–9819
Fernández A, Kardos J, Scott LR, Goto Y, Berry RS (2003) Structural defects and the diagnosis of amyloidogenic propensity. Proc Natl Acad Sci U S A 100:6446–6451
Fernandez-Escamilla A-M, Rousseau F, Schymkowitz J, Serrano L (2004) Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat Biotechnol 22:1302–1306
Ferrone FA, Hofrichter J, Sunshine HR, Eaton WA (1980) Kinetic studies on photolysis-induced gelation of sickle cell hemoglobin suggest a new mechanism. Biophys J 32:361–380
Foderà V, Librizzi F, Groenning M, van de Weert M, Leone M (2008) Secondary nucleation and accessible surface in insulin amyloid fibril formation. J Phys Chem B 112:3853–3858
Fowler DM, Koulov AV, Balch WE, Kelly JW (2007) Functional amyloid – from bacteria to humans. Trends Biochem Sci 32:217–224
Frieden C, Goddette DW (1983) Polymerization of actin and actin-like systems: evaluation of the time course of polymerization in relation to the mechanism. Biochemistry (Mosc) 22:5836–5843
Galzitskaya OV (2009) Are the same or different amino acid residues responsible for correct and incorrect protein folding? Biochem Biokhimii͡a 74:186–193
Galzitskaya OV (2011a) Misfolded species involved regions which are involved in an early folding nucleus. In: Haggerty LM (ed) Protein struct. Nova Science Publishers, Hauppauge, pp 1–30
Galzitskaya OV (2011b) Regions which are responsible for swapping are also responsible for folding and misfolding. Open Biochem J 5:27–36
Galzitskaya OV, Finkelstein AV (1999) A theoretical search for folding/unfolding nuclei in three-dimensional protein structures. Proc Natl Acad Sci U S A 96:11299–11304
Galzitskaya OV, Garbuzynskiy SO (2008) Folding and aggregation features of proteins. In: O’Doherty CB, Byrne AC (eds) Protein misfolding. Nova Science Publishers, New York, pp 99–112
Galzitskaya OV, Surin AK, Nakamura H (2000) Optimal region of average side-chain entropy for fast protein folding. Protein Sci 9:580–586
Galzitskaya OV, Garbuzynskiy SO, Lobanov MY (2006) FoldUnfold: web server for the prediction of disordered regions in protein chain. Bioinformatics 22:2948–2949
Garbuzynskiy SO, Finkelstein AV, Galzitskaya OV (2004) Outlining folding nuclei in globular proteins. J Mol Biol 336:509–525
Garbuzynskiy SO, Lobanov MY, Galzitskaya OV (2010) FoldAmyloid: a method of prediction of amyloidogenic regions from protein sequence. Bioinformatics 26:326–332
Gasior P, Kotulska M (2014) FISH Amyloid – a new method for finding amyloidogenic segments in proteins based on site specific co-occurence of aminoacids. BMC Bioinformatics 15:54
Gertz MA, Rajkumar SV (eds) (2010) Amyloidosis: diagnosis and treatment. Humana Press, New York
Giehm L, Otzen DE (2010) Strategies to increase the reproducibility of protein fibrillization in plate reader assays. Anal Biochem 400:270–281
Gilead S, Gazit E (2005) Self-organization of short peptide fragments: from amyloid fibrils to nanoscale supramolecular assemblies. Supramol Chem 17:87–92
Goldstein RF, Stryer L (1986) Cooperative polymerization reactions. Analytical approximations, numerical examples, and experimental strategy. Biophys J 50:583–599
Hamodrakas SJ, Liappa C, Iconomidou VA (2007) Consensus prediction of amyloidogenic determinants in amyloid fibril-forming proteins. Int J Biol Macromol 41:295–300
Hayman SR, Bailey RJ, Jalal SM, Ahmann GJ, Dispenzieri A, Gertz MA, Greipp PR, Kyle RA, Lacy MQ, Rajkumar SV, Witzig TE, Lust JA, Fonseca R (2001) Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood 98:2266–2268
Hofrichter J, Ross PD, Eaton WA (1974) Kinetics and mechanism of deoxyhemoglobin S gelation: a new approach to understanding sickle cell disease. Proc Natl Acad Sci U S A 71:4864–4868
Idicula-Thomas S, Balaji PV (2005) Understanding the relationship between the primary structure of proteins and their amyloidogenic propensity: clues from inclusion body formation. Protein Eng Des Sel PEDS 18:175–180
Ivanova MI, Sawaya MR, Gingery M, Attinger A, Eisenberg D (2004) An amyloid-forming segment of beta2-microglobulin suggests a molecular model for the fibril. Proc Natl Acad Sci U S A 101:10584–10589
Jahn TR, Parker MJ, Homans SW, Radford SE (2006) Amyloid formation under physiological conditions proceeds via a native-like folding intermediate. Nat Struct Mol Biol 13:195–201
Jaroniec CP, MacPhee CE, Astrof NS, Dobson CM, Griffin RG (2002) Molecular conformation of a peptide fragment of transthyretin in an amyloid fibril. Proc Natl Acad Sci U S A 99:16748–16753
Jiménez JL, Guijarro JI, Orlova E, Zurdo J, Dobson CM, Sunde M, Saibil HR (1999) Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing. EMBO J 18:815–821
Jones S, Manning J, Kad NM, Radford SE (2003) Amyloid-forming peptides from beta2-microglobulin-Insights into the mechanism of fibril formation in vitro. J Mol Biol 325:249–257
Kajava AV, Baxa U, Wickner RB, Steven AC (2004) A model for Ure2p prion filaments and other amyloids: the parallel superpleated beta-structure. Proc Natl Acad Sci U S A 101:7885–7890
Kalebina TS, Plotnikova TA, Gorkovskii AA, Selyakh IO, Galzitskaya OV, Bezsonov EE, Gellissen G, Kulaev IS (2008) Amyloid-like properties of Saccharomyces cerevisiae cell wall glucantransferase Bgl2p: prediction and experimental evidences. Prion 2:91–96
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–489
Klimtchuk ES, Gursky O, Patel RS, Laporte KL, Connors LH, Skinner M, Seldin DC (2010) The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain. Biochemistry (Mosc) 49:9848–9857
Knowles TPJ, Waudby CA, Devlin GL, Cohen SIA, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM (2009) An analytical solution to the kinetics of breakable filament assembly. Science 326:1533–1537
Kovacs E, Tompa P, Liliom K, Kalmar L (2010) Dual coding in alternative reading frames correlates with intrinsic protein disorder. Proc Natl Acad Sci U S A 107:5429–5434
Kozhukh GV, Hagihara Y, Kawakami T, Hasegawa K, Naiki H, Goto Y (2002) Investigation of a peptide responsible for amyloid fibril formation of beta 2-microglobulin by achromobacter protease I. J Biol Chem 277:1310–1315
Krebs MR, Wilkins DK, Chung EW, Pitkeathly MC, Chamberlain AK, Zurdo J, Robinson CV, Dobson CM (2000) Formation and seeding of amyloid fibrils from wild-type hen lysozyme and a peptide fragment from the beta-domain. J Mol Biol 300:541–549
López de la Paz M, Serrano L (2004) Sequence determinants of amyloid fibril formation. Proc Natl Acad Sci U S A 101:87–92
Lu X, Wintrode PL, Surewicz WK (2007) Beta-sheet core of human prion protein amyloid fibrils as determined by hydrogen/deuterium exchange. Proc Natl Acad Sci U S A 104:1510–1515
Matouschek A, Kellis JT, Serrano L, Fersht AR (1989) Mapping the transition state and pathway of protein folding by protein engineering. Nature 340:122–126
Maurer-Stroh S, Debulpaep M, Kuemmerer N, Lopez de la Paz M, Martins IC, Reumers J, Morris KL, Copland A, Serpell L, Serrano L, Schymkowitz JWH, Rousseau F (2010) Exploring the sequence determinants of amyloid structure using position-specific scoring matrices. Nat Methods 7:237–242
Maury CP, Nurmiaho-Lassila EL (1992) Creation of amyloid fibrils from mutant Asn187 gelsolin peptides. Biochem Biophys Res Commun 183:227–231
Morris AM, Watzky MA, Finke RG (2009) Protein aggregation kinetics, mechanism, and curve-fitting: a review of the literature. Biochim Biophys Acta 1794:375–397
Muñoz V, Serrano L (1994) Elucidating the folding problem of helical peptides using empirical parameters. Nat Struct Biol 1:399–409
Nelson R, Sawaya MR, Balbirnie M, Madsen A, Riekel C, Grothe R, Eisenberg D (2005) Structure of the cross-beta spine of amyloid-like fibrils. Nature 435:773–778
Oosawa F, Asakura S, Hotta K, Imai N, Ooi T (1959) G-F transformation of actin as a fibrous condensation. J Polym Sci 37:323–336
Picotti P, De Franceschi G, Frare E, Spolaore B, Zambonin M, Chiti F, de Laureto PP, Fontana A (2007) Amyloid fibril formation and disaggregation of fragment 1–29 of apomyoglobin: insights into the effect of pH on protein fibrillogenesis. J Mol Biol 367:1237–1245
Rauscher S, Baud S, Miao M, Keeley FW, Pomès R (2006) Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Structure 14:1667–1676
Roland BP, Kodali R, Mishra R, Wetzel R (2013) A serendipitous survey of prediction algorithms for amyloidogenicity. Biopolymers 100:780–789
Ruschak AM, Miranker AD (2007) Fiber-dependent amyloid formation as catalysis of an existing reaction pathway. Proc Natl Acad Sci U S A 104:12341–12346
Sánchez IE, Tejero J, Gómez-Moreno C, Medina M, Serrano L (2006) Point mutations in protein globular domains: contributions from function, stability and misfolding. J Mol Biol 363:422–432
Selivanova OM, Suvorina MY, Dovidchenko NV, Eliseeva IA, Surin AK, Finkelstein AV, Schmatchenko VV, Galzitskaya OV (2014) How to determine the size of folding nuclei of protofibrils from the concentration dependence of the rate and lag-time of aggregation. II. Experimental application for insulin and LysPro insulin: aggregation morphology, kinetics, and sizes of nuclei. J Phys Chem B 118:1198–1206
Serio TR, Cashikar AG, Kowal AS, Sawicki GJ, Moslehi JJ, Serpell L, Arnsdorf MF, Lindquist SL (2000) Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289:1317–1321
Tartaglia GG, Vendruscolo M (2008) The Zyggregator method for predicting protein aggregation propensities. Chem Soc Rev 37:1395–1401
Tartaglia GG, Pellarin R, Cavalli A, Caflisch A (2005) Organism complexity anti-correlates with proteomic beta-aggregation propensity. Protein Sci 14:2735–2740
Tenidis K, Waldner M, Bernhagen J, Fischle W, Bergmann M, Weber M, Merkle ML, Voelter W, Brunner H, Kapurniotu A (2000) Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties. J Mol Biol 295:1055–1071
Thangakani AM, Kumar S, Nagarajan R, Velmurugan D, Gromiha MM (2014) GAP: towards almost 100 percent prediction for β-strand-mediated aggregating peptides with distinct morphologies. Bioinformatics 30:1983–1990
Thompson A, White AR, McLean C, Masters CL, Cappai R, Barrow CJ (2000) Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrP(C). J Neurosci Res 62:293–301
Trovato A, Chiti F, Maritan A, Seno F (2006) Insight into the structure of amyloid fibrils from the analysis of globular proteins. PLoS Comput Biol 2:e170
Tsolis AC, Papandreou NC, Iconomidou VA, Hamodrakas SJ (2013) A consensus method for the prediction of “Aggregation-Prone” peptides in globular proteins. PLoS One 8:e54175
Von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E (2000) Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A 97:5129–5134
Walsh I, Seno F, Tosatto SCE, Trovato A (2014) PASTA 2.0: an improved server for protein aggregation prediction. Nucleic Acids Res 42:W301–W307
Wang Q, Johnson JL, Agar NYR, Agar JN (2008) Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. PLoS Biol 6:e170
Wegner A, Savko P (1982) Fragmentation of actin filaments. Biochemistry 21:1909–1913
Wright CF, Teichmann SA, Clarke J, Dobson CM (2005) The importance of sequence diversity in the aggregation and evolution of proteins. Nature 438:878–881
Xue W-F, Homans SW, Radford SE (2008) Systematic analysis of nucleation-dependent polymerization reveals new insights into the mechanism of amyloid self-assembly. Proc Natl Acad Sci U S A 105:8926–8931
Yang H, Li J-J, Liu S, Zhao J, Jiang Y-J, Song A-X, Hu H-Y (2014) Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology. Sci Rep 4:6410
Yoon S, Welsh WJ (2004) Detecting hidden sequence propensity for amyloid fibril formation. Protein Sci 13:2149–2160
Zhu L, Zhang X-J, Wang L-Y, Zhou J-M, Perrett S (2003) Relationship between stability of folding intermediates and amyloid formation for the yeast prion Ure2p: a quantitative analysis of the effects of pH and buffer system. J Mol Biol 328:235–254
Zimmermann O, Hansmann UHE (2006) Support vector machines for prediction of dihedral angle regions. Bioinformatics 22:3009–3015
Acknowledgement
We are grateful to Dr. Olga Gursky for her valuable comments and editorial help. This study was supported by the Russian Science Foundation grant №14-14-00536.
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Dovidchenko, N.V., Galzitskaya, O.V. (2015). Computational Approaches to Identification of Aggregation Sites and the Mechanism of Amyloid Growth. In: Gursky, O. (eds) Lipids in Protein Misfolding. Advances in Experimental Medicine and Biology, vol 855. Springer, Cham. https://doi.org/10.1007/978-3-319-17344-3_9
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