Advertisement

Aggregation and degradation scales for prion-like domains: sequence features and context weigh in

  • Sean M. Cascarina
  • Eric D. Ross
Mini-Review

Abstract

Protein aggregation in vivo is generally combated by extensive proteostatic defenses. Many proteostasis factors specifically recognize aggregation-prone features and re-fold or degrade the targeted protein. However, protein aggregation is not uncommon, suggesting that some proteins employ evasive strategies to aggregate in spite of the proteostasis machinery. Therefore, in addition to understanding the inherent aggregation propensity of protein sequences, it is important to understand how these sequences affect proteostatic recognition and regulation in vivo. In a recent study, we used a genetic mutagenesis and screening approach to explore the aggregation or degradation promoting effects of the canonical amino acids in the context of G-rich and Q/N-rich prion-like domains (PrLDs). Our results indicate that aggregation propensity scales are strongly influenced by the interplay between specific PrLD features and proteostatic recognition. Here, we briefly review these results and expand upon their potential implications. In addition, a preliminary exploration of the yeast proteome suggests that these proteostatic regulation heuristics may influence the compositional features of native G-rich and Q/N-rich domains in yeast. These results improve our understanding of the features affecting the aggregation and proteostatic regulation of prion-like domains in a cellular context, and suggest that the sequence space for native prion-like domains may be shaped by proteostatic constraints.

Keywords

Proteostasis Protein aggregation Prion Prion-like Protein degradation Low complexity domain 

Notes

Acknowledgements

This work was supported by a grant from the National Science Foundation (MCB-1817622) to E.D.R.

References

  1. Afsar Minhas F, ul A, Ross ED, Ben-Hur A (2017) Amino acid composition predicts prion activity. PLoS Comput Biol 13:1–20.  https://doi.org/10.1371/journal.pcbi.1005465 CrossRefGoogle Scholar
  2. Alberti S, Halfmann R, King O et al (2009) A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137:146–158CrossRefGoogle Scholar
  3. Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11:301–307.  https://doi.org/10.1038/nrm2873 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Cascarina SM, Ross ED (2018) Proteome-scale relationships between local amino acid composition and protein fates and functions. PLOS Comput Biol 14:e1006256.  https://doi.org/10.1371/journal.pcbi.1006256 CrossRefPubMedGoogle Scholar
  5. Cascarina SM, Paul KR, Ross ED (2017) Manipulating the aggregation activity of human prion-like proteins. Prion 11:323–331.  https://doi.org/10.1080/19336896.2017.1356560 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cascarina SM, Paul KR, Machihara S, Ross ED (2018) Sequence features governing aggregation or degradation of prion-like proteins. PLOS Genet 14:e1007517.  https://doi.org/10.1371/journal.pgen.1007517 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chakravarty AK, Jarosz DF (2018) More than just a phase: prions at the crossroads of epigenetic inheritance and evolutionary change. J Mol Biol.  https://doi.org/10.1016/j.jmb.2018.07.017 CrossRefPubMedGoogle Scholar
  8. Chernova TA, Kiktev DA, Romanyuk AV et al (2017a) Yeast short-lived actin-associated protein forms a metastable prion in response to thermal stress. Cell Rep 18:751–761.  https://doi.org/10.1016/j.celrep.2016.12.082 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chernova TA, Wilkinson KD, Chernoff YO (2017b) Prions, chaperones, and proteostasis in yeast. Cold Spring Harb Perspect Biol 9:a023663.  https://doi.org/10.1101/cshperspect.a023663 CrossRefPubMedGoogle Scholar
  10. Chuang E, Hori AM, Hesketh CD, Shorter J (2018) Amyloid assembly and disassembly. J Cell Sci 131:jcs189928.  https://doi.org/10.1242/jcs.189928 CrossRefPubMedGoogle Scholar
  11. Costanzo M, Zurzolo C (2013) The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration. Biochem J 452:1–17.  https://doi.org/10.1042/BJ20121898 CrossRefPubMedGoogle Scholar
  12. Derkatch IL, Bradley ME, Hong JY, Liebman SW (2001) Prions affect the appearance of other prions: the story of [PIN(+)]. Cell 106:171–182CrossRefGoogle Scholar
  13. Du Z, Park KK-W, Yu H et al (2008) Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae. Nat Genet 40:460–465.  https://doi.org/10.1038/ng.112 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Espinosa Angarica V, Ventura S, Sancho J (2013) Discovering putative prion sequences in complete proteomes using probabilistic representations of Q/N-rich domains. BMC Genom 14:316.  https://doi.org/10.1186/1471-2164-14-316 CrossRefGoogle Scholar
  15. Flynn GC, Pohl J, Flocco MT, Rothman JE (1991) Peptide-binding specificity of the molecular chaperone BiP. Nature 353:726–730.  https://doi.org/10.1038/353726a0 CrossRefPubMedGoogle Scholar
  16. Fredrickson EK, Rosenbaum JC, Locke MN et al (2011) Exposed hydrophobicity is a key determinant of nuclear quality control degradation. Mol Biol Cell 22:2384–2395.  https://doi.org/10.1091/mbc.E11-03-0256 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fredrickson EK, Gallagher PS, Candadai SVC, Gardner RG (2013) Substrate recognition in nuclear protein quality control degradation is governed by exposed hydrophobicity that correlates with aggregation and insolubility. J Biol Chem 288:6130–6139.  https://doi.org/10.1074/jbc.M112.406710 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Halfmann R, Wright J, Alberti S et al (2012) Prion formation by a yeast GLFG nucleoporin. Prion 6:391–399CrossRefGoogle Scholar
  19. Harrison PM, Gerstein M (2003) A method to assess compositional bias in biological sequences and its application to prion-like glutamine/asparagine-rich domains in eukaryotic proteomes. Genome Biol 4:R40CrossRefGoogle Scholar
  20. Harrison AF, Shorter J (2017) RNA-binding proteins with prion-like domains in health and disease. Biochem J 474:1417–1438.  https://doi.org/10.1042/BCJ20160499 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Holmes BB, Diamond MI (2012) Cellular mechanisms of protein aggregate propagation. Curr Opin Neurol 25:721–726.  https://doi.org/10.1097/WCO.0b013e32835a3ee0 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Karagoz GE, Duarte AM, Akoury E et al (2014) Hsp90–Tau complex reveals molecular basis for specificity in chaperone action. Cell 156:963–974.  https://doi.org/10.1016/j.cell.2014.01.037 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Karagöz GE, Rüdiger SGD (2015) Hsp90 interaction with clients. Trends Biochem Sci 40:117–125.  https://doi.org/10.1016/j.tibs.2014.12.002 CrossRefPubMedGoogle Scholar
  24. Kim HJ, Kim NC, Wang YD et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473.  https://doi.org/10.1038/nature11922 CrossRefPubMedPubMedCentralGoogle Scholar
  25. King OD, Gitler AD, Shorter J (2012) The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res 26:61–80.  https://doi.org/10.1016/j.brainres.2012.01.016 CrossRefGoogle Scholar
  26. Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in aging and disease. J Cell Biol 217:51–63.  https://doi.org/10.1083/jcb.201709072 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Lancaster AK, Nutter-Upham A, Lindquist S, King OD (2014) PLAAC: a web and command-line application to identify proteins with prion-like amino acid composition. Bioinformatics 30:2501–2502.  https://doi.org/10.1093/bioinformatics/btu310 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lee K-H, Zhang P, Kim HJ et al (2016) C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167:774–788.e17.  https://doi.org/10.1016/j.cell.2016.10.002 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Li YR, King OD, Shorter J, Gitler AD (2013) Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201:361–372.  https://doi.org/10.1083/jcb.201302044 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ling S-C, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438.  https://doi.org/10.1016/j.neuron.2013.07.033 CrossRefPubMedPubMedCentralGoogle Scholar
  31. MacLea KS, Paul KR, Ben-Musa Z et al (2015) Distinct amino acid compositional requirements for formation and maintenance of the [PSI+] prion in yeast. Mol Cell Biol 35:899–911.  https://doi.org/10.1128/MCB.01020-14 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Molliex A, Temirov J, Lee J et al (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163:123–133.  https://doi.org/10.1016/j.cell.2015.09.015 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Patel BK, Gavin-Smyth J, Liebman SW (2009) The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion. Nat Cell Biol 11:344–349.  https://doi.org/10.1038/ncb1843 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Paul KR, Molliex A, Cascarina S et al (2017) Effects of mutations on the aggregation propensity of the human prion-like protein hnRNPA2B1. Mol Cell Biol.  https://doi.org/10.1128/MCB.00652-16 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Ramaswami M, Taylor JP, Parker R (2013) Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154:727–736.  https://doi.org/10.1016/j.cell.2013.07.038 CrossRefPubMedGoogle Scholar
  36. Ross ED, Baxa U, Wickner RB (2004) Scrambled prion domains form prions and amyloid. Mol Cell Biol 24:7206–7213CrossRefGoogle Scholar
  37. Ross ED, Edskes HK, Terry MJ, Wickner RB (2005) Primary sequence independence for prion formation. Proc Natl Acad Sci USA 102:12825–12830CrossRefGoogle Scholar
  38. Rudiger S, Buchberger A, Bukau B (1997) Interaction of Hsp70 chaperones with substrates. Nat Struct Biol 4:342–349CrossRefGoogle Scholar
  39. Rüdiger S, Germeroth L, Schneider-Mergener J, Bukau B (1997) Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. EMBO J 16:1501–1507.  https://doi.org/10.1093/emboj/16.7.1501 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Rüdiger S, Schneider-Mergener J, Bukau B (2001) Its substrate specificity characterizes the DnaJ co-chaperone as a scanning factor for the DnaK chaperone. EMBO J 20:1042–1050.  https://doi.org/10.1093/emboj/20.5.1042 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ryzhova TA, Sopova JV, Zadorsky SP et al (2018) Screening for amyloid proteins in the yeast proteome. Curr Genet 64:469–478.  https://doi.org/10.1007/s00294-017-0759-7 CrossRefPubMedGoogle Scholar
  42. Saio T, Guan X, Rossi P et al (2014) Structural basis for protein antiaggregation activity of the trigger factor chaperone. Science 344:1250494.  https://doi.org/10.1126/science.1250494 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Sondheimer N, Lindquist S (2000) Rnq1: an epigenetic modifier of protein function in yeast. Mol Cell 5:163–172.  https://doi.org/10.1016/S1097-2765(00)80412-8 CrossRefPubMedGoogle Scholar
  44. Suzuki G, Shimazu N, Tanaka M (2012) A yeast prion, Mod5, promotes acquired drug resistance and cell survival under environmental stress. Science 336:355–359.  https://doi.org/10.1126/science.1219491 CrossRefPubMedGoogle Scholar
  45. Taylor JP, Brown RH Jr, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539:197–206.  https://doi.org/10.1038/nature20413 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Toombs JA, McCarty BR, Ross ED (2010) Compositional determinants of prion formation in yeast. Mol Cell Biol 30:319–332.  https://doi.org/10.1128/MCB.01140-09 CrossRefPubMedGoogle Scholar
  47. Wickner RB (1994) [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264:566–569.  https://doi.org/10.1126/science.7909170 CrossRefPubMedGoogle Scholar
  48. Willmund F, del Alamo M, Pechmann S et al (2013) The cotranslational function of ribosome-associated Hsp70 in eukaryotic protein homeostasis. Cell 152:196–209.  https://doi.org/10.1016/j.cell.2012.12.001 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Wisniewski BT, Sharma J, Legan ER et al (2018) Toxicity and infectivity: insights from de novo prion formation. Curr Genet 64:117–123.  https://doi.org/10.1007/s00294-017-0736-1 CrossRefPubMedGoogle Scholar
  50. Xiang S, Kato M, Wu LC et al (2015) The LC domain of hnRNPA2 adopts similar conformations in hydrogel polymers, liquid-like droplets, and nuclei. Cell 163:829–839.  https://doi.org/10.1016/j.cell.2015.10.040 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyColorado State UniversityFort CollinsUSA

Personalised recommendations