Biophysical Reviews

, Volume 10, Issue 2, pp 503–516 | Cite as

Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

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Abstract

In his Nobel Lecture, Anfinsen stated “the native conformation is determined by the totality of interatomic interactions and hence by the amino acid sequence, in a given environment.” As aqueous solutions and membrane systems co-exist in cells, proteins are classified into membrane and non-membrane proteins, but whether one can transform one into the other remains unknown. Intriguingly, many well-folded non-membrane proteins are converted into “insoluble” and toxic forms by aging- or disease-associated factors, but the underlying mechanisms remain elusive. In 2005, we discovered a previously unknown regime of proteins seemingly inconsistent with the classic “Salting-in” dogma: “insoluble” proteins including the integral membrane fragments could be solubilized in the ion-minimized water. We have thus successfully studied “insoluble” forms of ALS-causing P56S-MSP, L126Z-SOD1, nascent SOD1 and C71G-Profilin1, as well as E. coli S1 fragments. The results revealed that these “insoluble” forms are either unfolded or co-exist with their unfolded states. Most unexpectedly, these unfolded states acquire a novel capacity of interacting with membranes energetically driven by the formation of helices/loops over amphiphilic/hydrophobic regions which universally exit in proteins but are normally locked away in their folded native states. Our studies suggest that most, if not all, proteins contain segments which have the dual ability to fold into distinctive structures in aqueous and membrane environments. The abnormal membrane interaction might initiate disease and/or aging processes; and its further coupling with protein aggregation could result in radical proteotoxicity by forming inclusions composed of damaged membranous organelles and protein aggregates. Therefore, environment-transformable sequence–structure relationship may represent a general mechanism for proteotoxicity.

Keywords

Neurodegenerative diseases Aging Proteotoxicity Membrane interaction Liquid–liquid phase separation (LLPS) Prion-like domains 

Notes

Acknowledgements

I would like to thank all laboratory members, which is a long list, for their critical contributions. The studies are supported by Ministry of Education of Singapore (MOE) Tier 2 Grants MOE2015-T2-1-111 to Jianxing Song. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

Jianxing Song declares that he has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.

References

  1. Aguado-Llera D et al (2010) The basic helix-loop-helix region of human neurogenin 1 is a monomeric natively unfolded protein which forms a “fuzzy” complex. Biochemistry 49:1577–1589CrossRefPubMedGoogle Scholar
  2. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223–230CrossRefPubMedGoogle Scholar
  3. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431:805–810CrossRefPubMedGoogle Scholar
  4. Auluck PK, Caraveo G, Lindquist S (2010) α-Synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu Rev Cell Dev Biol 26:211–233CrossRefPubMedGoogle Scholar
  5. Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG (2006) Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington’s and Parkinson’s diseases. Proc Natl Acad Sci U S A 103:4246–4251CrossRefPubMedPubMedCentralGoogle Scholar
  6. Boeynaems S et al (2017) Phase separation of C9orf72 Dipeptide repeats perturbs stress granule dynamics. Mol Cell 65:1044–1055CrossRefPubMedPubMedCentralGoogle Scholar
  7. Brender JR, Salamekh S, Ramamoorthy A (2012) Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective. Acc Chem Res 45:454–462CrossRefPubMedGoogle Scholar
  8. Brown LR, Lauterwein J, Wüthrich K (1980) High-resolution 1H-NMR studies of self aggregation of melittin in aqueous solution. Biochim Biophys Acta 622:231–244CrossRefPubMedGoogle Scholar
  9. Burke KA, Janke AM, Rhine CL, Fawzi NL (2015) Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol Cell 60:231–241CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chan FT, Kaminski Schierle GS, Kumita JR, Bertoncini CW, Dobson CM, Kaminski CF (2013) Protein amyloids develop an intrinsic fluorescence signature during aggregation. Analyst 138:2156–2162CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chien P, Weissman JS (2001) Conformational diversity in a yeast prion dictates its seeding specificity. Nature 410:223–227CrossRefPubMedGoogle Scholar
  12. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333CrossRefPubMedGoogle Scholar
  13. Colvin MT et al (2016) Atomic resolution structure of Monomorphic Aβ42 Amyloid fibrils. J Am Chem Soc 138:9663–9674CrossRefPubMedPubMedCentralGoogle Scholar
  14. Conicella AE, Zerze GH, Mittal J, Fawzi NL (2016) ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24:1537–1549CrossRefPubMedPubMedCentralGoogle Scholar
  15. David DC, Ollikainen N, Trinidad JC, Cary MP, Burlingame AL, Kenyon C (2010) Widespread protein aggregation as an inherent part of aging in C. Elegans. PLoS Biol 8:e1000450CrossRefPubMedPubMedCentralGoogle Scholar
  16. Delak K et al (2009) The tooth enamel protein, porcine amelogenin, is an intrinsically disordered protein with an extended molecular configuration in the monomeric form. Biochemistry 48:2272CrossRefPubMedPubMedCentralGoogle Scholar
  17. Duttler S, Pechmann S, Frydman J (2013) Principles of cotranslational ubiquitination and quality control at the ribosome. Mol Cell 50:379–393CrossRefPubMedGoogle Scholar
  18. Elfrink K, Ollesch J, Stöhr J, Willbold D, Riesner D, Gerwert K (2008) Structural changes of membrane-anchored native PrP(C). Proc Natl Acad Sci U S A 105:10815–10819CrossRefPubMedPubMedCentralGoogle Scholar
  19. Futami J et al (2014) Denatured mammalian protein mixtures exhibit unusually high solubility in nucleic acid-free pure water. PLoS ONE 9:e113295CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ganassi M et al (2016) A surveillance function of the HSPB8-BAG3-HSP70 chaperone complex ensures stress granule integrity and dynamism. Mol Cell 63:796–810CrossRefPubMedGoogle Scholar
  21. Han TW et al (2012) Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149:768–779CrossRefPubMedGoogle Scholar
  22. Harrison AF, Shorter J (2017) RNA-binding proteins with prion-like domains in health and disease. Biochem J 474:1417–1438CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hartl FU (2016) Cellular homeostasis and aging. Annu Rev Biochem 85:1–4CrossRefPubMedGoogle Scholar
  24. Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA (2017) A phase separation model for transcriptional control. Cell 169:13–23CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kato M, McKnight SL (2017) Cross-β polymerization of low complexity sequence domains. Cold Spring Harb Perspect Biol 9.  https://doi.org/10.1101/cshperspect.a023598
  26. Kegel KB et al (2005) Huntingtin associates with acidic phospholipids at the plasma membrane. J Biol Chem 280:36464–36473CrossRefPubMedGoogle Scholar
  27. Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU (2013) Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 82:323–355CrossRefPubMedGoogle Scholar
  28. Kotler SA, Walsh P, Brender JR, Ramamoorthy A (2014) Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer’s disease. Chem Soc Rev 43:6692–6700CrossRefPubMedPubMedCentralGoogle Scholar
  29. Künze G, Barré P, Scheidt HA, Thomas L, Eliezer D, Huster D (2012) Binding of the three-repeat domain of tau to phospholipid membranes induces an aggregated-like state of the protein. Biochim Biophys Acta 1818:2302–2313CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ladokhin AS, White SH (1999) Folding of amphipathic alpha-helices on membranes: energetics of helix formation by melittin. J Mol Biol 285:1363–1369CrossRefPubMedGoogle Scholar
  31. Lauterwein J, Brown LR, Wüthrich K (1980) High-resolution. 1H-NMR studies of monomeric melittin in aqueous solution. Biochim Biophys Acta 622:219–230CrossRefPubMedGoogle Scholar
  32. Li M, Liu J, Ran X, Fang M, Shi J, Qin H, Goh JM, Song J (2006) Resurrecting abandoned proteins with pure water: CD and NMR studies of protein fragments solubilized in salt-free water. Biophys J 91:4201–4209CrossRefPubMedPubMedCentralGoogle Scholar
  33. Li Z, Yang Y, Zhan J, Dai L, Zhou Y (2013) Energy functions in de novo protein design: current challenges and future prospects. Annu Rev Biophys 42:315–335CrossRefPubMedGoogle Scholar
  34. Lim L, Song J (2016) SALS-linked WT-SOD1 adopts a highly similar helical conformation as FALS-causing L126Z-SOD1 in a membrane environment. Biochim Biophys Acta 1858:2223–2230CrossRefPubMedGoogle Scholar
  35. Lim L, Lee X, Song J (2015) Mechanism for transforming cytosolic SOD1 into integral membrane proteins of organelles by ALS causing mutations. Biochim Biophys Acta 1848:1–7CrossRefPubMedGoogle Scholar
  36. Lim L, Wei Y, Lu Y, Song J (2016a) ALS-causing mutations significantly perturb the self-assembly and interaction with nucleic acid of the intrinsically disordered Prion-like domain of TDP-43. PLoS Biol 14:e1002338CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lim L, Lu Y, Song J (2016b) Unlocked capacity of proteins to attack membranes characteristic of aggregation: the evil for diseases and aging from Pandora’s box. bioRxiv 071274.  http://dx.doi.org/10.1101/071274
  38. Lim L, Kang J, Song J (2017) ALS-causing rofiling-1-mutant forms a non-native helical structure in membrane environments. Biochim Biophys Acta Biomembr 1859:2161CrossRefGoogle Scholar
  39. Lin Y et al (2016) Toxic PR poly-Dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell 167:789–802CrossRefPubMedPubMedCentralGoogle Scholar
  40. Lindner AB, Madden R, Demarez A, Stewart EJ, Taddei F (2008) Asymmetric segregation of protein aggregates is associated with cellular aging and rejuvenation. Proc Natl Acad Sci U S A 105:3076–3081CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438CrossRefPubMedPubMedCentralGoogle Scholar
  42. Liu J et al (2004) Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 43:5–17CrossRefPubMedGoogle Scholar
  43. Lu Y, Lim L, Tan Y, Wang L, Song J (2016) Mechanisms of self-assembly and fibrillization of the prion-like domains. bioRxiv 065631.  https://doi.org/10.1101/065631
  44. Lu Y, Lim L, Song J (2017a) RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils. Sci Rep 7:1043CrossRefPubMedPubMedCentralGoogle Scholar
  45. Lu Y, Lim L, Song J. (2017b) RRM domain of ALS/FTD-causing FUS interacts with membrane: an anchor of membraneless organelles to membranes? bioRxiv 122671.  https://doi.org/10.1101/122671
  46. Mateju D et al (2017) An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. EMBO J 36:1669–1687CrossRefPubMedPubMedCentralGoogle Scholar
  47. McLendon PM, Robbins J (2015) Proteotoxicity and cardiac dysfunction. Circ Res 116:1863–1882CrossRefPubMedPubMedCentralGoogle Scholar
  48. Michelitsch MD, Weissman JS (2000) A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc Natl Acad Sci U S A 97:11910–11915CrossRefPubMedPubMedCentralGoogle Scholar
  49. Minor DL Jr, Kim PS (1996) Context-dependent secondary structure formation of a designed protein sequence. Nature 380:730–734CrossRefPubMedGoogle Scholar
  50. Monahan Z et al (2017) Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J 36:2951–2967CrossRefPubMedPubMedCentralGoogle Scholar
  51. Murakami T et al (2015) ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible Hydrogels into irreversible Hydrogels impairs RNP granule function. Neuron 88:678–690CrossRefPubMedPubMedCentralGoogle Scholar
  52. Murray DT, Kato M, Lin Y, Thurber KR, Hung I, McKnight SL, Tycko R. (2017) Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains. Cell 171(3):615–627.e16.  https://doi.org/10.1016/j.cell.2017.08.048
  53. Nachreiner T, Esser M, Tenten V, Troost D, Weis J, Krüttgen A (2010) Novel splice variants of the amyotrophic lateral sclerosisassociated gene VAPB expressed in human tissues. Biochem Biophys Res Commun 394:703–708CrossRefPubMedGoogle Scholar
  54. Nelson R et al (2005) Structure of the cross-beta spine of amyloid-like fibrils. Nature 435:773–778CrossRefPubMedPubMedCentralGoogle Scholar
  55. Patel A et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162:1066–1077CrossRefPubMedGoogle Scholar
  56. Perdigão N et al (2015) Unexpected features of the dark proteome. Proc Natl Acad Sci U S A 112:15898–15903CrossRefPubMedPubMedCentralGoogle Scholar
  57. Perutz MF, Johnson T, Suzuki M, Finch JT (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A 91:5355–5358CrossRefPubMedPubMedCentralGoogle Scholar
  58. Pinotsi D et al (2016) Proton transfer and structure-specific fluorescence in hydrogen bond-rich protein structures. J Am Chem Soc 138:3046–3057CrossRefPubMedGoogle Scholar
  59. Pinti DL (2005) The origin and evolution of the oceans. In Gargaud M et al. (eds) Lectures in Astrobiology. Springer, Berlin, pp 83–111. http://www.springer.com/gb/book/9783540262299
  60. Plaxco KW, Riddle DS, Grantcharova V, Baker D (1998) Simplified proteins: minimalist solutions to the ‘protein folding problem’. Curr Opin Struct Biol 8:80–85CrossRefPubMedGoogle Scholar
  61. Qin H, Wang W, Song J (2013a) ALS-causing P56S mutation and splicing variation on the hVAPB MSP domain transform its β-sandwich fold into lipid-interacting helical conformations. Biochem Biophys Res Commun 431:398–403CrossRefPubMedGoogle Scholar
  62. Qin H, Lim L, Wei Y, Gupta G, Song J (2013b) Resolving the paradox for protein aggregation diseases: NMR structure and dynamics of the membrane-embedded P56S-MSP causing ALS imply a common mechanism for aggregation-prone proteins to attack membranes. F1000Res 2:221PubMedGoogle Scholar
  63. Qin H, Lim LZ, Wei Y, Song J (2014) TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA. Proc Natl Acad Sci U S A 111:18619CrossRefPubMedPubMedCentralGoogle Scholar
  64. Rayman JB, Kandel ER (2017) Functional Prions in the Brain. Cold Spring Harb Perspect Biol 9(1).  https://doi.org/10.1101/cshperspect.a023671
  65. Riddle DS et al (1997) Functional rapidly folding proteins from simplified amino acid sequences. Nat Struct Biol 4:805–809CrossRefPubMedGoogle Scholar
  66. Rocklin GJ et al (2017) Global analysis of protein folding using massively parallel design, synthesis, and testing. Science 357:168–175CrossRefPubMedPubMedCentralGoogle Scholar
  67. Salonen LM, Ellermann M, Diederich F (2011) Aromatic rings in chemical and biological recognition: energetics and structures. Angew Chem Int Ed Engl 50:4808–4842CrossRefPubMedGoogle Scholar
  68. Sangwan S et al (2017) Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A 114:8770CrossRefPubMedPubMedCentralGoogle Scholar
  69. Schubert U, Antón LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774CrossRefPubMedGoogle Scholar
  70. Shahmoradian SH et al (2017) Lewy pathology in Parkinson’s disease consists of a crowded organellar membranous medley. bioRxiv.  https://doi.org/10.1101/137976
  71. Shi J, Lua S, Tong JS, Song J (2010) Elimination of the native structure and solubility of the hVAPB MSP domain by the Pro56Ser mutation that causes amyotrophic lateral sclerosis. Biochemistry 49:3887–3397CrossRefPubMedGoogle Scholar
  72. Shin Y, Brangwynne CP (2017) Liquid phase condensation in cell physiology and disease. Science 357:6357CrossRefGoogle Scholar
  73. Shorter J (2017) Liquidizing FUS via prion-like domain phosphorylation. EMBO J 36:2925–2927CrossRefPubMedGoogle Scholar
  74. Shorter J, Lindquist S (2005) Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6:435–450CrossRefPubMedGoogle Scholar
  75. Shukla A, Mukherjee S, Sharma S, Agrawal V, Radha Kishan KV, Guptasarma P (2004) A novel UV laser induced visible blue radiation from protein crystals and aggregates: scattering artifacts or fluorescence transitions of peptide electrons delocalized through hydrogen bonding? Arch Biochem Biophys 428:144–153CrossRefPubMedGoogle Scholar
  76. Song J (2009) Insight into “insoluble proteins” with pure water. FEBS Lett 583:953CrossRefPubMedGoogle Scholar
  77. Song J (2013) Why do proteins aggregate? “Intrinsically insoluble proteins” and “dark mediators” revealed by studies on “insoluble proteins” solubilized in pure water. F1000 Res 2:94Google Scholar
  78. Song J (2017) Transforming cytosolic proteins into “insoluble” and membrane-toxic forms triggering diseases/aging by genetic, pathological or environmental factors. Protein Pept Lett 24:294–306CrossRefPubMedGoogle Scholar
  79. Song J, Jamin N, Gilquin B, Vita C, Ménez A (1999) A gradual disruption of tight side-chain packing: 2D 1H-NMR characterization of acidinduced unfolding of CHABII. Nat Struct Biol 6:129–134CrossRefPubMedGoogle Scholar
  80. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisén J (2005) Retrospective birth dating of cells in humans. Cell 122:133–143CrossRefPubMedGoogle Scholar
  81. Sudhakaran IP, Ramaswami M (2017) Long-term memory consolidation: the role of RNA-binding proteins with prion-like domains. RNA Biol 14:568–586CrossRefPubMedGoogle Scholar
  82. Sun S et al (2015) Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc Natl Acad Sci U S A 112:E6993–E7002CrossRefPubMedPubMedCentralGoogle Scholar
  83. Teuling E et al (2007) Motor neuron disease-associated mutant vesicle-associated membrane protein- associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. J Neurosci 27:9801–9815CrossRefPubMedGoogle Scholar
  84. Tipping KW et al (2015) pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. Proc Natl Acad Sci U S A 112:5691–5696CrossRefPubMedPubMedCentralGoogle Scholar
  85. Ulmer TS et al (2005) Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem 280:9595–9603CrossRefPubMedGoogle Scholar
  86. van der Lee R et al (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631CrossRefPubMedPubMedCentralGoogle Scholar
  87. Vande Velde C, Miller TM, Cashman NR, Cleveland DW (2008) Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A 105:4022–4027CrossRefPubMedPubMedCentralGoogle Scholar
  88. Wei Z, Song J (2005) Molecular mechanism underlying the thermal stability and pH-induced unfolding of CHABII. J Mol Biol 348:205–218CrossRefPubMedGoogle Scholar
  89. White SH, Wimley WC (1999) Membrane protein folding and stability: physical principles. Annu Rev Biophys Biomol Struct 28:319–365CrossRefPubMedGoogle Scholar
  90. Willis MS, Patterson C (2013) Proteotoxicity and cardiac dysfunction--Alzheimer’s disease of the heart? N Engl J Med 368:455–464CrossRefPubMedGoogle Scholar
  91. Wootton JC (1994) Sequences with ‘unusual’ amino acid compositions. Curr Opin Struct Biol 4:413–421CrossRefGoogle Scholar
  92. Yang C et al (2016) Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity. Proc Natl Acad Sci U S A 113:E6209–E6218CrossRefPubMedPubMedCentralGoogle Scholar
  93. Zu JS, Deng HX, Lo TP, Mitsumoto H, Ahmed MS, Hung WY, Cai ZJ, Tainer JA, Siddique T (1997) Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis. Neurogenetics 1:65–71CrossRefPubMedGoogle Scholar

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© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Biological Sciences, Faculty of ScienceNational University of SingaporeSingaporeSingapore

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