The Structural Determinants of the Immunoglobulin Light Chain Amyloid Aggregation

  • Luis Del Pozo-YaunerEmail author
  • Baltazar Becerril
  • Adrián Ochoa-Leyva
  • Sandra Leticia Rodríguez-Ambriz
  • Julio Isael Pérez Carrión
  • Guadalupe Zavala-Padilla
  • Rosana Sánchez-López
  • Daniel Alejandro Fernández Velasco


The extracellular deposition of a monoclonal immunoglobulin light chain (LC) as insoluble fibrillar aggregates is the cause of the primary systemic amyloidosis, also known as light chain-derived (AL) amyloidosis. In this chapter the structural factors determining the potential of the LC to aggregate into amyloid fibrils are analyzed. In the first two sections, the relationship between protein aggregation and disease, as well as the causes and characteristics of the human amyloidoses are discussed. The role of protein misfolding in the fibril assembly pathway and the structural bases of the amyloid fibrils stability are also addressed. Then, the chapter focuses on the molecular causes of the amyloid aggregation of LC. The contribution of the somatic mutations and the identity of the variable gene segment encoding the LC to the propensity to form amyloid fibrils are discussed. The chapter summarizes the experimental evidence supporting the role of partially folded intermediates in the mechanism of AL fibril assembly, as well as the modulatory effect played by the variable region gene sequence on the aggregation behavior of the LC. Finally, the results of a recent study aimed to identify fibrillogenic regions in the λ6 recombinant variable domain protein 6aJL2 are presented.


Misfolding disease Amyloidosis Amyloid fibril Protein misfolding Non-native intermediate Protein aggregation Immunoglobulin light chain Lambda 6 subgroup Fibrillogenesis Profibrillogenic sequence 



This work was supported in part by grants from the Consejo Nacional de Ciencia y Tecnología (No. 169659) to L. del Pozo-Yauner.


  1. 1.
    Andras P, Andras C (2005) The origins of life—the ‘protein interaction world’ hypothesis: protein interactions were the first form of self-reproducing life and nucleic acids evolved later as memory molecules. Med Hypotheses 64(4):678–688. doi: 10.1016/j.mehy.2004.11.029 PubMedCrossRefGoogle Scholar
  2. 2.
    Pirlet K, Arthur-Goettig A (1999) Maintaining life and health by natural selection of protein molecules. J Theor Biol 201(1):75–85. doi: 10.1006/jtbi.1999.1015 PubMedCrossRefGoogle Scholar
  3. 3.
    Hingorani KS, Gierasch LM (2014) Comparing protein folding in vitro and in vivo: foldability meets the fitness challenge. Curr Opin Struct Biol 24:81–90. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  4. 4.
    Ferris SP, Kodali VK, Kaufman RJ (2014) Glycoprotein folding and quality-control mechanisms in protein-folding diseases. Dis Model Mech 7(3):331–341. doi: 10.1242/dmm.014589 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Dobson CM (2003) Protein folding and misfolding. Nature 426(6968):884–890. doi: 10.1038/nature02261 PubMedCrossRefGoogle Scholar
  6. 6.
    Hipp MS, Park SH, Hartl FU (2014) Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol 24(9):506–514. doi: 10.1016/j.tcb.2014.05.003 PubMedCrossRefGoogle Scholar
  7. 7.
    Stefani M, Dobson CM (2003) Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med 81(11):678–699. doi: 10.1007/s00109-003-0464-5 PubMedCrossRefGoogle Scholar
  8. 8.
    Papsdorf K, Richter K (2014) Protein folding, misfolding and quality control: the role of molecular chaperones. Essays Biochem 56:53–68. doi: 10.1042/bse0560053 PubMedCrossRefGoogle Scholar
  9. 9.
    Wyatt AR, Yerbury JJ, Ecroyd H, Wilson MR (2013) Extracellular chaperones and proteostasis. Annu Rev Biochem 82:295–322. doi: 10.1146/annurev-biochem-072711-163904 PubMedCrossRefGoogle Scholar
  10. 10.
    Gong H, Yang X, Zhao Y, Petersen RB, Liu X, Liu Y, Huang K (2014) Amyloidogenicity of p53: a hidden link between protein misfolding and cancer. Curr Protein Pept Sci 16(2):135–146CrossRefGoogle Scholar
  11. 11.
    Nagaraj NS, Singh OV, Merchant NB (2010) Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy. Expert Rev Proteomics 7(4):613–623. doi: 10.1586/epr.10.70 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Ashraf GM, Greig NH, Khan TA, Hassan I, Tabrez S, Shakil S, Sheikh IA, Zaidi SK, Akram M, Jabir NR, Firoz CK, Naeem A, Alhazza IM, Damanhouri GA, Kamal MA (2014) Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets 13(7):1280–1293PubMedCrossRefGoogle Scholar
  13. 13.
    Negahdar M, Aukrust I, Molnes J, Solheim MH, Johansson BB, Sagen JV, Dahl-Jorgensen K, Kulkarni RN, Sovik O, Flatmark T, Njolstad PR, Bjorkhaug L (2014) GCK-MODY diabetes as a protein misfolding disease: the mutation R275C promotes protein misfolding, self-association and cellular degradation. Mol Cell Endocrinol 382(1):55–65. doi: 10.1016/j.mce.2013.08.020 PubMedCrossRefGoogle Scholar
  14. 14.
    Iram A, Naeem A (2014) Protein folding, misfolding, aggregation and their implications in human diseases: discovering therapeutic ways to amyloid-associated diseases. Cell Biochem Biophys 70(1):51–61. doi: 10.1007/s12013-014-9904-9 PubMedCrossRefGoogle Scholar
  15. 15.
    Knowles TP, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15(6):384–396. doi: 10.1038/nrm3810 PubMedCrossRefGoogle Scholar
  16. 16.
    Sideras K, Gertz MA (2009) Amyloidosis. Adv Clin Chem 47:1–44PubMedCrossRefGoogle Scholar
  17. 17.
    Buxbaum JN, Linke RP (2012) A molecular history of the amyloidoses. J Mol Biol 421(2–3):142–159. doi: 10.1016/j.jmb.2012.01.024 PubMedCrossRefGoogle Scholar
  18. 18.
    Hazenberg BP (2013) Amyloidosis: a clinical overview. Rheum Dis Clin North Am 39(2):323–345. doi: 10.1016/j.rdc.2013.02.012 PubMedCrossRefGoogle Scholar
  19. 19.
    del Pozo-Yauner L, Wall JS, Gonzalez Andrade M, Sanchez-Lopez R, Rodriguez-Ambriz SL, Perez Carreon JI, Ochoa-Leyva A, Fernandez-Velasco DA (2014) The N-terminal strand modulates immunoglobulin light chain fibrillogenesis. Biochem Biophys Res Commun 443(2):495–499. doi: 10.1016/j.bbrc.2013.11.123 PubMedCrossRefGoogle Scholar
  20. 20.
    Baldwin AJ, Knowles TP, Tartaglia GG, Fitzpatrick AW, Devlin GL, Shammas SL, Waudby CA, Mossuto MF, Meehan S, Gras SL, Christodoulou J, Anthony-Cahill SJ, Barker PD, Vendruscolo M, Dobson CM (2011) Metastability of native proteins and the phenomenon of amyloid formation. J Am Chem Soc 133(36):14160–14163. doi: 10.1021/ja2017703 PubMedCrossRefGoogle Scholar
  21. 21.
    Thirumalai D, Reddy G (2011) Protein thermodynamics: are native proteins metastable? Nat Chem 3(12):910–911. doi: 10.1038/nchem.1207 PubMedCrossRefGoogle Scholar
  22. 22.
    Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181(4096):223–230PubMedCrossRefGoogle Scholar
  23. 23.
    Colon W, Lai Z, McCutchen SL, Miroy GJ, Strang C, Kelly JW (1996) FAP mutations destabilize transthyretin facilitating conformational changes required for amyloid formation. Ciba Found Symp 199:228–238; discussion 239–242PubMedGoogle Scholar
  24. 24.
    Maury CP, Nurmiaho-Lassila EL, Rossi H (1994) Amyloid fibril formation in gelsolin-derived amyloidosis. Definition of the amyloidogenic region and evidence of accelerated amyloid formation of mutant Asn-187 and Tyr-187 gelsolin peptides. Lab Invest 70(4):558–564PubMedGoogle Scholar
  25. 25.
    Martsev SP, Dubnovitsky AP, Vlasov AP, Hoshino M, Hasegawa K, Naiki H, Goto Y (2002) Amyloid fibril formation of the mouse V(L) domain at acidic pH. Biochemistry 41(10):3389–3395PubMedCrossRefGoogle Scholar
  26. 26.
    Mishra R, Sorgjerd K, Nystrom S, Nordigarden A, Yu YC, Hammarstrom P (2007) Lysozyme amyloidogenesis is accelerated by specific nicking and fragmentation but decelerated by intact protein binding and conversion. J Mol Biol 366(3):1029–1044. doi: 10.1016/j.jmb.2006.11.084 PubMedCrossRefGoogle Scholar
  27. 27.
    Jansen R, Dzwolak W, Winter R (2005) Amyloidogenic self-assembly of insulin aggregates probed by high resolution atomic force microscopy. Biophys J 88(2):1344–1353. doi: 10.1529/biophysj.104.048843 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Wiseman RL, Green NS, Kelly JW (2005) Kinetic stabilization of an oligomeric protein under physiological conditions demonstrated by a lack of subunit exchange: implications for transthyretin amyloidosis. Biochemistry 44(25):9265–9274. doi: 10.1021/bi050352o PubMedCrossRefGoogle Scholar
  29. 29.
    Serebryany E, King JA (2014) The betagamma-crystallins: native state stability and pathways to aggregation. Prog Biophys Mol Biol 115(1):32–41. doi: 10.1016/j.pbiomolbio.2014.05.002 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Hamada D, Dobson CM (2002) A kinetic study of beta-lactoglobulin amyloid fibril formation promoted by urea. Protein Sci 11(10):2417–2426. doi: 10.1110/ps.0217702 PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Fandrich 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(26):15463–15468. doi: 10.1073/pnas.0303758100 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Armen RS, Alonso DO, Daggett V (2004) Anatomy of an amyloidogenic intermediate: conversion of beta-sheet to alpha-sheet structure in transthyretin at acidic pH. Structure 12(10):1847–1863. doi: 10.1016/j.str.2004.08.005 PubMedCrossRefGoogle Scholar
  33. 33.
    Ferrao-Gonzales AD, Souto SO, Silva JL, Foguel D (2000) The preaggregated state of an amyloidogenic protein: hydrostatic pressure converts native transthyretin into the amyloidogenic state. Proc Natl Acad Sci U S A 97(12):6445–6450PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Gupta P, Deep S (2014) Intermediate conformation between native beta-sheet and non-native alpha-helix is a precursor of trifluoroethanol-induced aggregation of human carbonic anhydrase-II. Biochem Biophys Res Commun 449(1):126–131. doi: 10.1016/j.bbrc.2014.04.160 PubMedCrossRefGoogle Scholar
  35. 35.
    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(3):195–201. doi: 10.1038/nsmb1058 PubMedCrossRefGoogle Scholar
  36. 36.
    Kameda A, Hoshino M, Higurashi T, Takahashi S, Naiki H, Goto Y (2005) Nuclear magnetic resonance characterization of the refolding intermediate of beta2-microglobulin trapped by non-native prolyl peptide bond. J Mol Biol 348(2):383–397. doi: 10.1016/j.jmb.2005.02.050 PubMedCrossRefGoogle Scholar
  37. 37.
    Pallares I, Vendrell J, Aviles FX, Ventura S (2004) Amyloid fibril formation by a partially structured intermediate state of alpha-chymotrypsin. J Mol Biol 342(1):321–331. doi: 10.1016/j.jmb.2004.06.089 PubMedCrossRefGoogle Scholar
  38. 38.
    Santucci R, Sinibaldi F, Fiorucci L (2008) Protein folding, unfolding and misfolding: role played by intermediate states. Mini Rev Med Chem 8(1):57–62PubMedCrossRefGoogle Scholar
  39. 39.
    Vanderhaegen S, Fislage M, Domanska K, Versees W, Pardon E, Bellotti V, Steyaert J (2013) Structure of an early native-like intermediate of beta2-microglobulin amyloidogenesis. Protein Sci 22(10):1349–1357. doi: 10.1002/pro.2321 PubMedCentralPubMedGoogle Scholar
  40. 40.
    Agocs G, Szabo BT, Kohler G, Osvath S (2012) Comparing the folding and misfolding energy landscapes of phosphoglycerate kinase. Biophys J 102(12):2828–2834. doi: 10.1016/j.bpj.2012.05.006 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Harrison RS, Sharpe PC, Singh Y, Fairlie DP (2007) Amyloid peptides and proteins in review. Rev Physiol Biochem Pharmacol 159:1–77. doi: 10.1007/112_2007_0701 PubMedGoogle Scholar
  42. 42.
    Murphy RM (2007) Kinetics of amyloid formation and membrane interaction with amyloidogenic proteins. Biochim Biophys Acta 1768(8):1923–1934. doi: 10.1016/j.bbamem.2006.12.014 PubMedCrossRefGoogle Scholar
  43. 43.
    Sarkar N, Dubey VK (2013) Exploring critical determinants of protein amyloidogenesis: a review. J Pept Sci 19(9):529–536. doi: 10.1002/psc.2539 PubMedCrossRefGoogle Scholar
  44. 44.
    Neudecker P, Robustelli P, Cavalli A, Walsh P, Lundstrom P, Zarrine-Afsar A, Sharpe S, Vendruscolo M, Kay LE (2012) Structure of an intermediate state in protein folding and aggregation. Science 336(6079):362–366. doi: 10.1126/science.1214203 PubMedCrossRefGoogle Scholar
  45. 45.
    Ferreira ST, Chapeaurouge A, De Felice FG (2005) Stabilization of partially folded states in protein folding/misfolding transitions by hydrostatic pressure. Braz J Med Biol Res 38(8):1215–1222. doi:/S0100-879X2005000800009PubMedCrossRefGoogle Scholar
  46. 46.
    Ferreira ST, De Felice FG, Chapeaurouge A (2006) Metastable, partially folded states in the productive folding and in the misfolding and amyloid aggregation of proteins. Cell Biochem Biophys 44(3):539–548. doi: 10.1385/CBB:44:3:539 PubMedCrossRefGoogle Scholar
  47. 47.
    Jenkins DC, Sylvester ID, Pinheiro TJ (2008) The elusive intermediate on the folding pathway of the prion protein. FEBS J 275(6):1323–1335. doi: 10.1111/j.1742-4658.2008.06293.x PubMedCrossRefGoogle Scholar
  48. 48.
    Korzhnev DM, Religa TL, Banachewicz W, Fersht AR, Kay LE (2010) A transient and low-populated protein-folding intermediate at atomic resolution. Science 329(5997):1312–1316. doi: 10.1126/science.1191723 PubMedCrossRefGoogle Scholar
  49. 49.
    Neira JL (2013) NMR as a tool to identify and characterize protein folding intermediates. Arch Biochem Biophys 531(1–2):90–99. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  50. 50.
    Eichner T, Radford SE (2009) A generic mechanism of beta2-microglobulin amyloid assembly at neutral pH involving a specific proline switch. J Mol Biol 386(5):1312–1326PubMedCrossRefGoogle Scholar
  51. 51.
    Guo Z, Eisenberg D (2007) The mechanism of the amyloidogenic conversion of T7 endonuclease I. J Biol Chem 282(20):14968–14974. doi: 10.1074/jbc.M609514200 PubMedCrossRefGoogle Scholar
  52. 52.
    Nelson R, Eisenberg D (2006) Structural models of amyloid-like fibrils. Adv Protein Chem 73:235–282. doi: 10.1016/S0065-3233(06)73008-X PubMedCrossRefGoogle Scholar
  53. 53.
    Foss TR, Kelker MS, Wiseman RL, Wilson IA, Kelly JW (2005) Kinetic stabilization of the native state by protein engineering: implications for inhibition of transthyretin amyloidogenesis. J Mol Biol 347(4):841–854. doi: 10.1016/j.jmb.2005.01.050 PubMedCrossRefGoogle Scholar
  54. 54.
    Jahn TR, Radford SE (2005) The Yin and Yang of protein folding. FEBS J 272(23):5962–5970. doi: 10.1111/j.1742-4658.2005.05021.x PubMedCrossRefGoogle Scholar
  55. 55.
    Fawzi NL, Chubukov V, Clark LA, Brown S, Head-Gordon T (2005) Influence of denatured and intermediate states of folding on protein aggregation. Protein Sci 14(4):993–1003. doi: 10.1110/ps.041177505 PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Privalov PL (1996) Intermediate states in protein folding. J Mol Biol 258(5):707–725. doi: 10.1006/jmbi.1996.0280 PubMedCrossRefGoogle Scholar
  57. 57.
    Jimenez 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(4):815–821. doi: 10.1093/emboj/18.4.815 PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Makin OS, Serpell LC (2002) Examining the structure of the mature amyloid fibril. Biochem Soc Trans 30(4):521–525. doi:10.1042/PubMedCrossRefGoogle Scholar
  59. 59.
    Serpell LC, Sunde M, Fraser PE, Luther PK, Morris EP, Sangren O, Lundgren E, Blake CC (1995) Examination of the structure of the transthyretin amyloid fibril by image reconstruction from electron micrographs. J Mol Biol 254(2):113–118. doi: 10.1006/jmbi.1995.0604 PubMedCrossRefGoogle Scholar
  60. 60.
    Shivaprasad S, Wetzel R (2006) Analysis of amyloid fibril structure by scanning cysteine mutagenesis. Methods Enzymol 413:182–198. doi: 10.1016/S0076-6879(06)13010-4 PubMedCrossRefGoogle Scholar
  61. 61.
    Shivji AP, Brown F, Davies MC, Jennings KH, Roberts CJ, Tendler S, Wilkinson MJ, Williams PM (1995) Scanning tunnelling microscopy studies of beta-amyloid fibril structure and assembly. FEBS Lett 371(1):25–28PubMedCrossRefGoogle Scholar
  62. 62.
    Tycko R (2000) Solid-state NMR as a probe of amyloid fibril structure. Curr Opin Chem Biol 4(5):500–506PubMedCrossRefGoogle Scholar
  63. 63.
    Bedrood S, Li Y, Isas JM, Hegde BG, Baxa U, Haworth IS, Langen R (2012) Fibril structure of human islet amyloid polypeptide. J Biol Chem 287(8):5235–5241. doi: 10.1074/jbc.M111.327817 PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Fitzpatrick AW, Debelouchina GT, Bayro MJ, Clare DK, Caporini MA, Bajaj VS, Jaroniec CP, Wang L, Ladizhansky V, Muller SA, MacPhee CE, Waudby CA, Mott HR, De Simone A, Knowles TP, Saibil HR, Vendruscolo M, Orlova EV, Griffin RG, Dobson CM (2013) Atomic structure and hierarchical assembly of a cross-beta amyloid fibril. Proc Natl Acad Sci U S A 110(14):5468–5473. doi: 10.1073/pnas.1219476110 PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C, Grothe R, Eisenberg D (2005) Structure of the cross-beta spine of amyloid-like fibrils. Nature 435(7043):773–778. doi: 10.1038/nature03680 PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Sachse C, Xu C, Wieligmann K, Diekmann S, Grigorieff N, Fandrich M (2006) Quaternary structure of a mature amyloid fibril from Alzheimer’s Abeta(1-40) peptide. J Mol Biol 362(2):347–354. doi: 10.1016/j.jmb.2006.07.011 PubMedCrossRefGoogle Scholar
  67. 67.
    Bonar L, Cohen AS, Skinner MM (1969) Characterization of the amyloid fibril as a cross-beta protein. Proc Soc Exp Biol Med 131(4):1373–1375PubMedCrossRefGoogle Scholar
  68. 68.
    Kirschner DA, Abraham C, Selkoe DJ (1986) X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. Proc Natl Acad Sci U S A 83(2):503–507PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Serpell LC, Berriman J, Jakes R, Goedert M, Crowther RA (2000) Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci U S A 97(9):4897–4902PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Jahn TR, Makin OS, Morris KL, Marshall KE, Tian P, Sikorski P, Serpell LC (2010) The common architecture of cross-beta amyloid. J Mol Biol 395(4):717–727. doi: 10.1016/j.jmb.2009.09.039 PubMedCrossRefGoogle Scholar
  71. 71.
    Balbirnie M, Grothe R, Eisenberg DS (2001) An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated beta-sheet structure for amyloid. Proc Natl Acad Sci U S A 98(5):2375–2380. doi: 10.1073/pnas.041617698 PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Diaz-Avalos R, Long C, Fontano E, Balbirnie M, Grothe R, Eisenberg D, Caspar DL (2003) Cross-beta order and diversity in nanocrystals of an amyloid-forming peptide. J Mol Biol 330(5):1165–1175PubMedCrossRefGoogle Scholar
  73. 73.
    Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT, Madsen AO, Riekel C, Eisenberg D (2007) Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447(7143):453–457. doi: 10.1038/nature05695 PubMedCrossRefGoogle Scholar
  74. 74.
    Eisenberg D, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148(6):1188–1203. doi: 10.1016/j.cell.2012.02.022 PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Goldschmidt L, Teng PK, Riek R, Eisenberg D (2010) Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc Natl Acad Sci U S A 107(8):3487–3492. doi: 10.1073/pnas.0915166107 PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Lesne SE (2013) Breaking the code of amyloid-beta oligomers. Int J Cell Biol 2013:950783. doi: 10.1155/2013/950783 PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Esteras-Chopo A, Serrano L, Lopez de la Paz M (2005) The amyloid stretch hypothesis: recruiting proteins toward the dark side. Proc Natl Acad Sci U S A 102(46):16672–16677. doi: 10.1073/pnas.0505905102 PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Pastor MT, Esteras-Chopo A, Serrano L (2007) Hacking the code of amyloid formation: the amyloid stretch hypothesis. Prion 1(1):9–14PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Hammarstrom P, Jiang X, Hurshman AR, Powers ET, Kelly JW (2002) Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc Natl Acad Sci U S A 99(Suppl 4):16427–16432. doi: 10.1073/pnas.202495199 PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Hurshman Babbes AR, Powers ET, Kelly JW (2008) Quantification of the thermodynamically linked quaternary and tertiary structural stabilities of transthyretin and its disease-associated variants: the relationship between stability and amyloidosis. Biochemistry 47(26):6969–6984. doi: 10.1021/bi800636q PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Richardson JS, Richardson DC (2002) Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci U S A 99(5):2754–2759. doi: 10.1073/pnas.052706099 PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Solomon A (1986) Light chains of immunoglobulins: structural-genetic correlates. Blood 68(3):603–610PubMedGoogle Scholar
  83. 83.
    Carlsson M (1994) [150 years of Bence Jones protein. A reliable marker for multiple myeloma]. Lakartidningen 91(44):3993–3995PubMedGoogle Scholar
  84. 84.
    Glenner GG, Harbaugh J, Ohma JI, Harada M, Cuatrecasas P (1970) An amyloid protein: the amino-terminal variable fragment of an immunoglobulin light chain. Biochem Biophys Res Commun 41(5):1287–1289PubMedCrossRefGoogle Scholar
  85. 85.
    Palladini G, Comenzo RL (2012) The challenge of systemic immunoglobulin light-chain amyloidosis (Al). Subcell Biochem 65:609–642. doi: 10.1007/978-94-007-5416-4_22 PubMedCrossRefGoogle Scholar
  86. 86.
    Bellotti V, Mangione P, Merlini G (2000) Review: immunoglobulin light chain amyloidosis—the archetype of structural and pathogenic variability. J Struct Biol 130(2–3):280–289. doi: 10.1006/jsbi.2000.4248 PubMedCrossRefGoogle Scholar
  87. 87.
    Ramirez-Alvarado M (2012) Amyloid formation in light chain amyloidosis. Curr Top Med Chem 12(22):2523–2533PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Buxbaum J (1992) Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease. Hematol Oncol Clin North Am 6(2):323–346PubMedGoogle Scholar
  89. 89.
    Rocken C, Hegenbarth V, Schmitz M, Stix B, Schade G, Mohnert A, Roessner A (2000) Plasmacytoma of the tonsil with AL amyloidosis: evidence of post-fibrillogenic proteolysis of the fibril protein. Virchows Arch 436(4):336–344PubMedCrossRefGoogle Scholar
  90. 90.
    Solomon A, Weiss DT, Murphy CL, Hrncic R, Wall JS, Schell M (1998) Light chain-associated amyloid deposits comprised of a novel kappa constant domain. Proc Natl Acad Sci U S A 95(16):9547–9551PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Yamamoto K, Yagi H, Lee YH, Kardos J, Hagihara Y, Naiki H, Goto Y (2010) The amyloid fibrils of the constant domain of immunoglobulin light chain. FEBS Lett 584(15):3348–3353. doi: 10.1016/j.febslet.2010.06.019 PubMedCrossRefGoogle Scholar
  92. 92.
    Solomon A, Weiss DT, Williams TK (1992) Experimental model of human light-chain-associated disease. Curr Top Microbiol Immunol 182:261–267PubMedGoogle Scholar
  93. 93.
    Wall J, Murphy CL, Solomon A (1999) In vitro immunoglobulin light chain fibrillogenesis. Methods Enzymol 309:204–217PubMedCrossRefGoogle Scholar
  94. 94.
    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 49(45):9848–9857. doi: 10.1021/bi101351c PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Stenstad T, Magnus JH, Kolset SO, Cornwell GG 3rd, Husby G (1991) Macromolecular properties of glycosaminoglycans in primary AL amyloid fibril extracts of lymphoid tissue origin. Scand J Immunol 34(5):611–617PubMedCrossRefGoogle Scholar
  96. 96.
    Stevens FJ, Kisilevsky R (2000) Immunoglobulin light chains, glycosaminoglycans, and amyloid. Cell Mol Life Sci 57(3):441–449PubMedCrossRefGoogle Scholar
  97. 97.
    Jiang X, Myatt E, Lykos P, Stevens FJ (1997) Interaction between glycosaminoglycans and immunoglobulin light chains. Biochemistry 36(43):13187–13194. doi: 10.1021/bi970408h PubMedCrossRefGoogle Scholar
  98. 98.
    Martin DJ, Ramirez-Alvarado M (2011) Glycosaminoglycans promote fibril formation by amyloidogenic immunoglobulin light chains through a transient interaction. Biophys Chem 158(1):81–89. doi: 10.1016/j.bpc.2011.05.011 PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    McLaughlin RW, De Stigter JK, Sikkink LA, Baden EM, Ramirez-Alvarado M (2006) The effects of sodium sulfate, glycosaminoglycans, and Congo red on the structure, stability, and amyloid formation of an immunoglobulin light-chain protein. Protein Sci 15(7):1710–1722. doi: 10.1110/ps.051997606 PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Ren R, Hong Z, Gong H, Laporte K, Skinner M, Seldin DC, Costello CE, Connors LH, Trinkaus-Randall V (2010) Role of glycosaminoglycan sulfation in the formation of immunoglobulin light chain amyloid oligomers and fibrils. J Biol Chem 285(48):37672–37682. doi: 10.1074/jbc.M110.149575 PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Blancas-Mejia LM, Hammernik J, Marin-Argany M, Ramirez-Alvarado M (2014) Differential effects on light chain amyloid formation depend on mutations and type of glycosaminoglycans. J Biol Chem 290(8):4953–4965. doi: 10.1074/jbc.M114.615401 PubMedCrossRefGoogle Scholar
  102. 102.
    Booth DR, Sunde M, Bellotti V, Robinson CV, Hutchinson WL, Fraser PE, Hawkins PN, Dobson CM, Radford SE, Blake CC, Pepys MB (1997) Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385(6619):787–793. doi: 10.1038/385787a0 PubMedCrossRefGoogle Scholar
  103. 103.
    Sekijima Y, Hammarstrom P, Matsumura M, Shimizu Y, Iwata M, Tokuda T, Ikeda S, Kelly JW (2003) Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology. Lab Invest 83(3):409–417PubMedCrossRefGoogle Scholar
  104. 104.
    Sukhanova A, Poly S, Shemetov A, Bronstein I, Nabiev I (2012) Implications of protein structure instability: from physiological to pathological secondary structure. Biopolymers 97(8):577–588. doi: 10.1002/bip.22055 PubMedCrossRefGoogle Scholar
  105. 105.
    Wei L, Berman Y, Castano EM, Cadene M, Beavis RC, Devi L, Levy E (1998) Instability of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type. J Biol Chem 273(19):11806–11814PubMedCrossRefGoogle Scholar
  106. 106.
    Baden EM, Owen BA, Peterson FC, Volkman BF, Ramirez-Alvarado M, Thompson JR (2008) Altered dimer interface decreases stability in an amyloidogenic protein. J Biol Chem 283(23):15853–15860. doi: 10.1074/jbc.M705347200 PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Poshusta TL, Katoh N, Gertz MA, Dispenzieri A, Ramirez-Alvarado M (2013) Thermal stability threshold for amyloid formation in light chain amyloidosis. Int J Mol Sci 14(11):22604–22617. doi: 10.3390/ijms141122604 PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Raffen R, Dieckman LJ, Szpunar M, Wunschl C, Pokkuluri PR, Dave P, Wilkins Stevens P, Cai X, Schiffer M, Stevens FJ (1999) Physicochemical consequences of amino acid variations that contribute to fibril formation by immunoglobulin light chains. Protein Sci 8(3):509–517. doi: 10.1110/ps.8.3.509 PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Wall J, Schell M, Murphy C, Hrncic R, Stevens FJ, Solomon A (1999) Thermodynamic instability of human lambda 6 light chains: correlation with fibrillogenicity. Biochemistry 38(42):14101–14108PubMedCrossRefGoogle Scholar
  110. 110.
    Wetzel R (1997) Domain stability in immunoglobulin light chain deposition disorders. Adv Protein Chem 50:183–242PubMedCrossRefGoogle Scholar
  111. 111.
    French DL, Laskov R, Scharff MD (1989) The role of somatic hypermutation in the generation of antibody diversity. Science 244(4909):1152–1157PubMedCrossRefGoogle Scholar
  112. 112.
    Perfetti V, Ubbiali P, Vignarelli MC, Diegoli M, Fasani R, Stoppini M, Lisa A, Mangione P, Obici L, Arbustini E, Merlini G (1998) Evidence that amyloidogenic light chains undergo antigen-driven selection. Blood 91(8):2948–2954PubMedGoogle Scholar
  113. 113.
    Baden EM, Randles EG, Aboagye AK, Thompson JR, Ramirez-Alvarado M (2008) Structural insights into the role of mutations in amyloidogenesis. J Biol Chem 283(45):30950–30956. doi: 10.1074/jbc.M804822200 PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Hurle MR, Helms LR, Li L, Chan W, Wetzel R (1994) A role for destabilizing amino acid replacements in light-chain amyloidosis. Proc Natl Acad Sci U S A 91(12):5446–5450PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Dealwis C, Wall J (2004) Towards understanding the structure-function relationship of human amyloid disease. Curr Drug Targets 5(2):159–171PubMedCrossRefGoogle Scholar
  116. 116.
    Gonzalez-Andrade M, Becerril-Lujan B, Sanchez-Lopez R, Cecena-Alvarez H, Perez-Carreon JI, Ortiz E, Fernandez-Velasco DA, del Pozo-Yauner L (2013) Mutational and genetic determinants of lambda6 light chain amyloidogenesis. FEBS J 280(23):6173–6183. doi: 10.1111/febs.12538 PubMedCrossRefGoogle Scholar
  117. 117.
    Randles EG, Thompson JR, Martin DJ, Ramirez-Alvarado M (2009) Structural alterations within native amyloidogenic immunoglobulin light chains. J Mol Biol 389(1):199–210. doi: 10.1016/j.jmb.2009.04.010 PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Souillac PO, Uversky VN, Millett IS, Khurana R, Doniach S, Fink AL (2002) Effect of association state and conformational stability on the kinetics of immunoglobulin light chain amyloid fibril formation at physiological pH. J Biol Chem 277(15):12657–12665. doi: 10.1074/jbc.M109230200 PubMedCrossRefGoogle Scholar
  119. 119.
    Takahashi N, Hasegawa K, Yamaguchi I, Okada H, Ueda T, Gejyo F, Naiki H (2002) Establishment of a first-order kinetic model of light chain-associated amyloid fibril extension in vitro. Biochim Biophys Acta 1601(1):110–120PubMedCrossRefGoogle Scholar
  120. 120.
    Wang F, Sen S, Zhang Y, Ahmad I, Zhu X, Wilson IA, Smider VV, Magliery TJ, Schultz PG (2013) Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation. Proc Natl Acad Sci U S A 110(11):4261–4266. doi: 10.1073/pnas.1301810110 PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    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(6950):805–808. doi: 10.1038/nature01891 PubMedCrossRefGoogle Scholar
  122. 122.
    Retter I, Althaus HH, Munch R, Muller W (2005) VBASE2, an integrative V gene database. Nucleic Acids Res 33(Database issue):D671–D674. doi: 10.1093/nar/gki088 PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Ignatovich O, Tomlinson IM, Jones PT, Winter G (1997) The creation of diversity in the human immunoglobulin V(lambda) repertoire. J Mol Biol 268(1):69–77. doi: 10.1006/jmbi.1997.0956 PubMedCrossRefGoogle Scholar
  124. 124.
    Collins AM, Wang Y, Singh V, Yu P, Jackson KJ, Sewell WA (2008) The reported germline repertoire of human immunoglobulin kappa chain genes is relatively complete and accurate. Immunogenetics 60(11):669–676. doi: 10.1007/s00251-008-0325-z PubMedCrossRefGoogle Scholar
  125. 125.
    Perfetti V, Casarini S, Palladini G, Vignarelli MC, Klersy C, Diegoli M, Ascari E, Merlini G (2002) Analysis of V(lambda)-J(lambda) expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r (lambdaIII) as a new amyloid-associated germline gene segment. Blood 100(3):948–953. doi: 10.1182/blood-2002-01-0114 PubMedCrossRefGoogle Scholar
  126. 126.
    Bodi K, Prokaeva T, Spencer B, Eberhard M, Connors LH, Seldin DC (2009) AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences. Amyloid 16(1):1–8. doi: 10.1080/13506120802676781 PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Ozaki S, Abe M, Wolfenbarger D, Weiss DT, Solomon A (1994) Preferential expression of human lambda-light-chain variable-region subgroups in multiple myeloma, AL amyloidosis, and Waldenstrom’s macroglobulinemia. Clin Immunol Immunopathol 71(2):183–189PubMedCrossRefGoogle Scholar
  128. 128.
    Abraham RS, Geyer SM, Price-Troska TL, Allmer C, Kyle RA, Gertz MA, Fonseca R (2003) Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome in light chain-associated amyloidosis (AL). Blood 101(10):3801–3808. doi: 10.1182/blood-2002-09-2707 PubMedCrossRefGoogle Scholar
  129. 129.
    Comenzo RL, Wally J, Kica G, Murray J, Ericsson T, Skinner M, Zhang Y (1999) Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation. Br J Haematol 106(3):744–751PubMedCrossRefGoogle Scholar
  130. 130.
    Solomon A, Frangione B, Franklin EC (1982) Bence Jones proteins and light chains of immunoglobulins. Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda). J Clin Invest 70(2):453–460PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    del Pozo Yauner L, Ortiz E, Sanchez R, Sanchez-Lopez R, Guereca L, Murphy CL, Allen A, Wall JS, Fernandez-Velasco DA, Solomon A, Becerril B (2008) Influence of the germline sequence on the thermodynamic stability and fibrillogenicity of human lambda 6 light chains. Proteins 72(2):684–692. doi: 10.1002/prot.21934 PubMedCrossRefGoogle Scholar
  132. 132.
    Blancas-Mejia LM, Tellez LA, del Pozo-Yauner L, Becerril B, Sanchez-Ruiz JM, Fernandez-Velasco DA (2009) Thermodynamic and kinetic characterization of a germ line human lambda6 light-chain protein: the relation between unfolding and fibrillogenesis. J Mol Biol 386(4):1153–1166. doi: 10.1016/j.jmb.2008.12.069 PubMedCrossRefGoogle Scholar
  133. 133.
    Khurana R, Gillespie JR, Talapatra A, Minert LJ, Ionescu-Zanetti C, Millett I, Fink AL (2001) Partially folded intermediates as critical precursors of light chain amyloid fibrils and amorphous aggregates. Biochemistry 40(12):3525–3535PubMedCrossRefGoogle Scholar
  134. 134.
    Solomon A, Weiss DT, Kattine AA (1991) Nephrotoxic potential of Bence Jones proteins. N Engl J Med 324(26):1845–1851. doi: 10.1056/NEJM199106273242603 PubMedCrossRefGoogle Scholar
  135. 135.
    Solomon A, Weiss DT, Pepys MB (1992) Induction in mice of human light-chain-associated amyloidosis. Am J Pathol 140(3):629–637PubMedCentralPubMedGoogle Scholar
  136. 136.
    Sikkink LA, Ramirez-Alvarado M (2008) Biochemical and aggregation analysis of Bence Jones proteins from different light chain diseases. Amyloid 15(1):29–39. doi: 10.1080/13506120701815324 PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Frare E, Polverino De Laureto P, Zurdo J, Dobson CM, Fontana A (2004) A highly amyloidogenic region of hen lysozyme. J Mol Biol 340(5):1153–1165. doi: 10.1016/j.jmb.2004.05.056 PubMedCrossRefGoogle Scholar
  138. 138.
    Iconomidou VA, Leontis A, Hoenger A, Hamodrakas SJ (2013) Identification of a novel ‘aggregation-prone’/‘amyloidogenic determinant’ peptide in the sequence of the highly amyloidogenic human calcitonin. FEBS Lett 587(6):569–574. doi: 10.1016/j.febslet.2013.01.031 PubMedCrossRefGoogle Scholar
  139. 139.
    Ivanova MI, Thompson MJ, Eisenberg D (2006) A systematic screen of beta(2)-microglobulin and insulin for amyloid-like segments. Proc Natl Acad Sci U S A 103(11):4079–4082. doi: 10.1073/pnas.0511298103 PubMedCentralPubMedCrossRefGoogle Scholar
  140. 140.
    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(4):1055–1071. doi: 10.1006/jmbi.1999.3422 PubMedCrossRefGoogle Scholar
  141. 141.
    Thompson MJ, Sievers SA, Karanicolas J, Ivanova MI, Baker D, Eisenberg D (2006) The 3D profile method for identifying fibril-forming segments of proteins. Proc Natl Acad Sci U S A 103(11):4074–4078. doi: 10.1073/pnas.0511295103 PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    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(1):e54175. doi: 10.1371/journal.pone.0054175 PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Kabat EA, Wu TT, Perry HM, Gottesman KS, Foeller C (1991) Sequences of proteins of immunological interest, vol 5, 5th edn. National Institutes of Health, BethesdaGoogle Scholar
  144. 144.
    Beerten J, Van Durme J, Gallardo R, Capriotti E, Serpell L, Rousseau F, Schymkowitz J (2015) WALTZ-DB: a benchmark database of amyloidogenic hexapeptides. Bioinformatics 31(10):1698–1700. doi: 10.1093/bioinformatics/btv027 PubMedCrossRefGoogle Scholar
  145. 145.
    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 JW, Rousseau F (2010) Exploring the sequence determinants of amyloid structure using position-specific scoring matrices. Nat Methods 7(3):237–242. doi: 10.1038/nmeth.1432 PubMedCrossRefGoogle Scholar
  146. 146.
    del Pozo Yauner L, Ortiz E, Becerril B (2006) The CDR1 of the human lambdaVI light chains adopts a new canonical structure. Proteins 62(1):122–129. doi: 10.1002/prot.20779 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Luis Del Pozo-Yauner
    • 1
    Email author
  • Baltazar Becerril
    • 2
  • Adrián Ochoa-Leyva
    • 1
  • Sandra Leticia Rodríguez-Ambriz
    • 3
  • Julio Isael Pérez Carrión
    • 1
  • Guadalupe Zavala-Padilla
    • 2
  • Rosana Sánchez-López
    • 2
  • Daniel Alejandro Fernández Velasco
    • 4
  1. 1.Laboratorio de Estructura de ProteínasInstituto Nacional de Medicina GenómicaTlalpan, MéxicoMexico
  2. 2.Instituto de Biotecnología UNAMCuernavacaMexico
  3. 3.Centro de Desarrollo de Productos Bióticos, IPNYautepecMexico
  4. 4.Facultad de Medicina UNAMMéxicoMexico

Personalised recommendations