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PMID: 19345193 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

A systematic survey identifies prions and illuminates sequence features of prionogenic proteins.

Cell ·Vol. 137 ·No. 1 ·2009-04-03 ·Pages 146-58

Alberti S, Halfmann R, King O, Kapila A, Lindquist S

Abstract

Prions are proteins that convert between structurally and functionally distinct states, one or more of which is transmissible. In yeast, this ability allows them to act as non-Mendelian elements of phenotypic inheritance. To further our understanding of prion biology, we conducted a bioinformatic proteome-wide survey for prionogenic proteins in S. cerevisiae, followed by experimental investigations of 100 prion candidates. We found an unexpected amino acid bias in aggregation-prone candidates and discovered that 19 of these could also form prions. At least one of these prion proteins, Mot3, produces a bona fide prion in its natural context that increases population-level phenotypic heterogeneity. The self-perpetuating states of these proteins present a vast source of heritable phenotypic variation that increases the adaptability of yeast populations to diverse environments.

MeSH Terms
Amino Acid Sequence Amyloid/metabolism Asparagine/metabolism Cytosol/metabolism Genome, Fungal Glutamine/metabolism Heat-Shock Proteins/metabolism Molecular Sequence Data Peptide Termination Factors Phenotype Prions/analysis,chemistry,genetics,metabolism Proteome/analysis Saccharomyces cerevisiae/genetics,metabolism Saccharomyces cerevisiae Proteins/analysis,chemistry,genetics,metabolism Transcription Factors/chemistry,metabolism
Chemicals
Amyloid Heat-Shock Proteins MOT3 protein, S cerevisiae Peptide Termination Factors Prions Proteome SUP35 protein, S cerevisiae Saccharomyces cerevisiae Proteins Transcription Factors Glutamine HsP104 protein, S cerevisiae Asparagine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Alberti Simon
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Halfmann Randal
King Oliver
Kapila Atul
Lindquist Susan
References (77)
77 references, click to expand
  1. Appearance and propagation of polyglutamine-based amyloids in yeast: tyrosine residues enable polymer fragmentation.
    J Biol Chem. 2008 May 30;283(22):15185-92 PMID: 18381282
  2. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology.
    Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604-9 PMID: 10200309
  3. Dissection and design of yeast prions.
    PLoS Biol. 2004 Apr;2(4):E86 PMID: 15045026
  4. Protein-only transmission of three yeast prion strains.
    Nature. 2004 Mar 18;428(6980):319-23 PMID: 15029195
  5. Chaperone-dependent amyloid assembly protects cells from prion toxicity.
    Proc Natl Acad Sci U S A. 2008 May 20;105(20):7206-11 PMID: 18480252
  6. Epigenetic control of polyamines by the prion [PSI+].
    Nat Cell Biol. 2008 Sep;10(9):1069-75 PMID: 19160487
  7. Prions as adaptive conduits of memory and inheritance.
    Nat Rev Genet. 2005 Jun;6(6):435-50 PMID: 15931169
  8. Sequence determinants of amyloid fibril formation.
    Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):87-92 PMID: 14691246
  9. Mot3 is a transcriptional repressor of ergosterol biosynthetic genes and is required for normal vacuolar function in Saccharomyces cerevisiae.
    EMBO J. 2002 Aug 1;21(15):4114-24 PMID: 12145211
  10. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits.
    Nature. 2004 Sep 9;431(7005):184-7 PMID: 15311209
  11. Oligopeptide-repeat expansions modulate 'protein-only' inheritance in yeast.
    Nature. 1999 Aug 5;400(6744):573-6 PMID: 10448860
  12. Self-replication and scrapie.
    Nature. 1967 Sep 2;215(5105):1043-4 PMID: 4964084
  13. Screening for amyloid aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis.
    J Vis Exp. 2008 Jul 16;(17): PMID: 19066511
  14. The chemical genomic portrait of yeast: uncovering a phenotype for all genes.
    Science. 2008 Apr 18;320(5874):362-5 PMID: 18420932
  15. Interactions among prions and prion "strains" in yeast.
    Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16392-9 PMID: 12149514
  16. The [PSI+] prion of Saccharomyces cerevisiae can be propagated by an Hsp104 orthologue from Candida albicans.
    Eukaryot Cell. 2006 Feb;5(2):217-25 PMID: 16467463
  17. Genetical aspects of [URE3], a non-mitochondrial, cytoplasmically inherited mutation in yeast.
    Mol Gen Genet. 1975;136(4):327-35 PMID: 16095000
  18. A non-Q/N-rich prion domain of a foreign prion, [Het-s], can propagate as a prion in yeast.
    Mol Cell. 2007 Jul 6;27(1):67-77 PMID: 17612491
  19. Strain-specific morphologies of yeast prion amyloid fibrils.
    Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10165-70 PMID: 16006506
  20. Prion generation in vitro: amyloid of Ure2p is infectious.
    EMBO J. 2005 Sep 7;24(17):3082-92 PMID: 16096644
  21. "Prion-proof" for [PIN+]: infection with in vitro-made amyloid aggregates of Rnq1p-(132-405) induces [PIN+].
    J Mol Biol. 2007 Jan 19;365(3):773-82 PMID: 17097676
  22. Creating a protein-based element of inheritance.
    Science. 2000 Jan 28;287(5453):661-4 PMID: 10650001
  23. Cellular factors important for the de novo formation of yeast prions.
    Biochem Soc Trans. 2008 Oct;36(Pt 5):1083-7 PMID: 18793193
  24. Stopped-flow kinetics reveal multiple phases of thioflavin T binding to Alzheimer beta (1-40) amyloid fibrils.
    Arch Biochem Biophys. 1997 Jun 15;342(2):306-16 PMID: 9186492
  25. The physical basis of how prion conformations determine strain phenotypes.
    Nature. 2006 Aug 3;442(7102):585-9 PMID: 16810177
  26. Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution.
    Protein Sci. 1993 Mar;2(3):404-10 PMID: 8453378
  27. Analysis of amyloid aggregates using agarose gel electrophoresis.
    Methods Enzymol. 2006;412:33-48 PMID: 17046650
  28. Modulation of prion formation, aggregation, and toxicity by the actin cytoskeleton in yeast.
    Mol Cell Biol. 2006 Jan;26(2):617-29 PMID: 16382152
  29. A new approach for isolating cell wall mutants in Saccharomyces cerevisiae by screening for hypersensitivity to calcofluor white.
    Yeast. 1994 Aug;10(8):1019-30 PMID: 7992502
  30. Reciprocal regulation of anaerobic and aerobic cell wall mannoprotein gene expression in Saccharomyces cerevisiae.
    J Bacteriol. 2001 May;183(9):2881-7 PMID: 11292809
  31. Prion and non-prion amyloids of the HET-s prion forming domain.
    J Mol Biol. 2007 Jul 20;370(4):768-83 PMID: 17532341
  32. Converting the prion protein: what makes the protein infectious.
    Biochim Biophys Acta. 2007 Jun;1772(6):692-703 PMID: 16935473
  33. Insights into the mechanism of prion propagation.
    Curr Opin Struct Biol. 2008 Feb;18(1):52-9 PMID: 18243685
  34. Characterizing the conformational ensemble of monomeric polyglutamine.
    Proteins. 2006 May 1;63(2):297-311 PMID: 16299774
  35. Visualization of aggregation of the Rnq1 prion domain and cross-seeding interactions with Sup35NM.
    J Biol Chem. 2007 Jan 19;282(3):1779-87 PMID: 17121829
  36. Prions.
    Biochemistry (Mosc). 2007 Dec;72(13):1519-36 PMID: 18282140
  37. Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI(+)] prion.
    Cell. 2001 Jul 27;106(2):183-94 PMID: 11511346
  38. [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae.
    Science. 1994 Apr 22;264(5158):566-9 PMID: 7909170
  39. A suite of Gateway cloning vectors for high-throughput genetic analysis in Saccharomyces cerevisiae.
    Yeast. 2007 Oct;24(10):913-9 PMID: 17583893
  40. Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast.
    J Bacteriol. 1979 Sep;139(3):1068-71 PMID: 225301
  41. Deletion of new covalently linked cell wall glycoproteins alters the electrophoretic mobility of phosphorylated wall components of Saccharomyces cerevisiae.
    J Bacteriol. 1999 May;181(10):3076-86 PMID: 10322008
  42. A natively unfolded yeast prion monomer adopts an ensemble of collapsed and rapidly fluctuating structures.
    Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2649-54 PMID: 17299036
  43. Stress and prions: lessons from the yeast model.
    FEBS Lett. 2007 Jul 31;581(19):3695-701 PMID: 17509571
  44. Prion domains: sequences, structures and interactions.
    Nat Cell Biol. 2005 Nov;7(11):1039-44 PMID: 16385730
  45. Prion switching in response to environmental stress.
    PLoS Biol. 2008 Nov 25;6(11):e294 PMID: 19067491
  46. A yeast prion provides a mechanism for genetic variation and phenotypic diversity.
    Nature. 2000 Sep 28;407(6803):477-83 PMID: 11028992
  47. Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism.
    EMBO J. 1999 Apr 1;18(7):1974-81 PMID: 10202160
  48. Amyloid aggregates of the HET-s prion protein are infectious.
    Proc Natl Acad Sci U S A. 2002 May 28;99(11):7402-7 PMID: 12032295
  49. Prions affect the appearance of other prions: the story of [PIN(+)].
    Cell. 2001 Jul 27;106(2):171-82 PMID: 11511345
  50. FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded.
    Bioinformatics. 2005 Aug 15;21(16):3435-8 PMID: 15955783
  51. Hsp104, Hsp70 and Hsp40 interplay regulates formation, growth and elimination of Sup35 prions.
    EMBO J. 2008 Oct 22;27(20):2712-24 PMID: 18833196
  52. Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells.
    Science. 1995 Oct 6;270(5233):93-5 PMID: 7569955
  53. Primary sequence independence for prion formation.
    Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12825-30 PMID: 16123127
  54. 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. 2000 Oct 24;97(22):11910-5 PMID: 11050225
  55. Yeast prions [URE3] and [PSI+] are diseases.
    Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10575-80 PMID: 16024723
  56. Mot3, a Zn finger transcription factor that modulates gene expression and attenuates mating pheromone signaling in Saccharomyces cerevisiae.
    Genetics. 1998 Jun;149(2):879-92 PMID: 9611199
  57. Rnq1: an epigenetic modifier of protein function in yeast.
    Mol Cell. 2000 Jan;5(1):163-72 PMID: 10678178
  58. Scrambled prion domains form prions and amyloid.
    Mol Cell Biol. 2004 Aug;24(16):7206-13 PMID: 15282319
  59. Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae.
    Nat Genet. 2008 Apr;40(4):460-5 PMID: 18362884
  60. The evolution of bet-hedging adaptations to rare scenarios.
    Theor Popul Biol. 2007 Dec;72(4):560-75 PMID: 17915273
  61. The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments.
    Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1498-503 PMID: 9990052
  62. Propagation of yeast prions.
    Nat Rev Mol Cell Biol. 2003 Nov;4(11):878-90 PMID: 14625537
  63. Reversion analysis of [psi-] mutations in Saccharomyces cerevisiae.
    Genet Res. 1981 Apr;37(2):173-82 PMID: 7021322
  64. Prion domain initiation of amyloid formation in vitro from native Ure2p.
    Science. 1999 Feb 26;283(5406):1339-43 PMID: 10037606
  65. A method to assess compositional bias in biological sequences and its application to prion-like glutamine/asparagine-rich domains in eukaryotic proteomes.
    Genome Biol. 2003;4(6):R40 PMID: 12801414
  66. Novel proteinaceous infectious particles cause scrapie.
    Science. 1982 Apr 9;216(4542):136-44 PMID: 6801762
  67. Evolutionary conservation of prion-forming abilities of the yeast Sup35 protein.
    Mol Microbiol. 2000 Feb;35(4):865-76 PMID: 10692163
  68. Molecular basis of a yeast prion species barrier.
    Cell. 2000 Jan 21;100(2):277-88 PMID: 10660050
  69. Vegetative incompatibility in filamentous fungi: Podospora and Neurospora provide some clues.
    Curr Opin Microbiol. 2000 Dec;3(6):608-12 PMID: 11121781
  70. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast.
    Science. 1996 Aug 2;273(5275):622-6 PMID: 8662547
  71. Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae.
    Cell. 1997 May 30;89(5):811-9 PMID: 9182769
  72. Nucleated conformational conversion and the replication of conformational information by a prion determinant.
    Science. 2000 Aug 25;289(5483):1317-21 PMID: 10958771
  73. Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+].
    Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16446-53 PMID: 12461168
  74. Nonsense suppression in yeast cells overproducing Sup35 (eRF3) is caused by its non-heritable amyloids.
    J Biol Chem. 2005 Mar 11;280(10):8808-12 PMID: 15618222
  75. A neuronal isoform of the aplysia CPEB has prion-like properties.
    Cell. 2003 Dec 26;115(7):879-91 PMID: 14697205
  76. Dependence and independence of [PSI(+)] and [PIN(+)]: a two-prion system in yeast?
    EMBO J. 2000 May 2;19(9):1942-52 PMID: 10790361
  77. Evidence for the prion hypothesis: induction of the yeast [PSI+] factor by in vitro- converted Sup35 protein.
    Science. 2000 Jul 28;289(5479):595-9 PMID: 10915616
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.02.044
Published
2009-04-03
Pages
146-58
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2683788
Subset
IM
Grants
NIGMS NIH HHS · GM025874 · United States
NIGMS NIH HHS · R01 GM025874-30 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R37 GM025874 · United States
NIGMS NIH HHS · R01 GM025874 · United States
Corrections
CommentIn
PMID: 19345180
External Links
PubMed source DOI: 10.1016/j.cell.2009.02.044 PMC Full Text View journal details
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