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Gene Review

SUP35  -  translation termination factor GTPase eRF3

Saccharomyces cerevisiae S288c

Synonyms: ERF-3, ERF2, ERF3, Eukaryotic peptide chain release factor GTP-binding subunit, G1 to S phase transition protein 1, ...
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Disease relevance of SUP35

  • In vitro, Ure2p and Sup35p form amyloid, a filamentous protein structure, high in beta-sheet with a characteristic green birefringent staining by the dye Congo Red. Amyloid deposits are a cardinal feature of Alzheimer's disease, non-insulin-dependent diabetes mellitus, the transmissible spongiform encephalopathies, and many other diseases [1].
  • One and the same chaperone alteration, substitution A503V in the middle region of the chaperone Hsp104, exhibited opposite effects on one of the endogenous prions ([PSI(+)], the prion form of Sup35) and on polyglutamines, increasing aggregate size and toxicity in the former case and decreasing them in the latter case [2].
  • We show here that Ure2p is a soluble protein that can assemble into fibers that are similar to the fibers observed in the case of PrP in its scrapie prion filaments form or that form on Sup35 self-assembly [3].
  • Examples of functional links are given for a protein family of previously unknown function, a protein whose human homologues are implicated in colon cancer and the yeast prion Sup35 [4].
  • We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli [5].

High impact information on SUP35


Chemical compound and disease context of SUP35


Biological context of SUP35

  • Analysis of the naturally occurring alleles of RNQ1 and SUP35 indicated that the various polymorphisms identified were associated with DNA tandem repeats (6, 12, 33, 42 or 57 bp) within the coding sequences [10].
  • We have previously shown that multicopy plasmids containing the complete SUP35 gene are able to induce the appearance of the non-Mendelian factor [PSI] [11].
  • 2) [PSI] propagation requires SUP35 and [URE3] propagation requires URE2 with recessive chromosomal mutants having the same phenotypes as the presence of the respective dominant non-Mendelian element [12].
  • Guanidine reduces stop codon read-through caused by missense mutations in SUP35 or SUP45 [13].
  • [PSI] is a non-Mendelian enhancer of readthrough of translational termination similar in its effects to some mutations in the chromosomal SUP35 gene [12].

Anatomical context of SUP35


Associations of SUP35 with chemical compounds

  • Clearly, anti-suppression caused by growth in the presence of GuHCl is not sufficient to distinguish missense mutations in SUP35 or SUP45, from [PSI(+)] [13].
  • We have demonstrated that ribosomes from the four suppressors SUP35, SUP44, SUP45 and SUP46 translate polyuridylate templates in vitro with higher errors than ribosomes from the normal stain, and that this misreading is substantially enhanced by the antibiotic paromomycin [18].
  • In a Sla1(-) background, [PSI] curing by dimethylsulfoxide or excess Hsp104 is increased, while translational readthrough and de novo [PSI] formation induced by excess Sup35 or Sup35N are decreased [19].
  • The N-terminal parts of Ure2p and Sup35p (the "prion domains") are responsible for prion formation and propagation and are rich in asparagine and glutamine residues [20].
  • The model is consistent with current biophysical, biochemical, and structural data (notably, mass-per-unit-length measurements by scanning transmission electron microscopy that gave one subunit rise per 0.47 nm) and is readily adaptable to other amyloids, for instance the core of Sup35p filaments and glutamine expansions in huntingtin [21].

Physical interactions of SUP35

  • Two sites for Sup45p binding were found within Sup35p: one is formed by the N and M domains, and the other is located within the C domain [22].
  • Here, we demonstrate that the yeast prion protein Sup35 interacts with various proteins of the actin cortical cytoskeleton that are involved in endocytosis [16].
  • Hsp104 binds to yeast Sup35 prion fiber but needs other factor(s) to sever it [23].

Enzymatic interactions of SUP35

  • We propose that Hsp104p plays a role in establishing stable [psi+] inheritance by splitting up Sup35p aggregates and thus ensuring equidistribution of the prion-like Sup35p isoform to daughter cells at cell divisions [24].

Regulatory relationships of SUP35

  • We now show that SUP45 overexpression inhibits the induction of [PSI+] by Sup35p overproduction in [PIN+] strains, but has no effect on the propagation of [PSI+] or on the [PIN] status of the cells [25].
  • We confirmed that a genetic interaction exists between eRF3 and Pab1p and showed that Pab1p overexpression enhances the efficiency of termination in SUP35 (eRF3) mutant and [PSI(+)] cells [26].
  • In contrast, Ssa1p together with either of its Hsp40 cochaperones blocks Sup35p polymerization [27].
  • To test this model, we used live imaging of Sup35p-GFP to follow the changes that occur in [PSI+] cells after the addition of guanidine to inactivate Hsp104 [28].

Other interactions of SUP35

  • The ability of Sup45p C-terminally tagged with (His)6 to specifically precipitate Sup35p from a cell lysate was used to confirm this interaction in vitro [29].
  • Indeed, like [PSI+], the maintenance of [ETA+] requires the N-terminal region of Sup35p and depends on an appropriate level of the chaperone protein Hsp104 [30].
  • We find here that Dcp1p can interact with the release factor eRF3p (Sup35p) in Saccharomyces cerevisiae [31].
  • Genetic study of interactions between the cytoskeletal assembly protein sla1 and prion-forming domain of the release factor Sup35 (eRF3) in Saccharomyces cerevisiae [19].
  • Tethered poly(A)-binding protein (Pab1p), used as a mimic of a normal 3'-UTR, recruits the termination factor Sup35p (eRF3) and stabilizes nonsense-containing mRNAs [32].

Analytical, diagnostic and therapeutic context of SUP35


  1. Prions in Saccharomyces and Podospora spp.: protein-based inheritance. Wickner, R.B., Taylor, K.L., Edskes, H.K., Maddelein, M.L., Moriyama, H., Roberts, B.T. Microbiol. Mol. Biol. Rev. (1999) [Pubmed]
  2. Modulation of prion-dependent polyglutamine aggregation and toxicity by chaperone proteins in the yeast model. Gokhale, K.C., Newnam, G.P., Sherman, M.Y., Chernoff, Y.O. J. Biol. Chem. (2005) [Pubmed]
  3. Structural characterization of Saccharomyces cerevisiae prion-like protein Ure2. Thual, C., Komar, A.A., Bousset, L., Fernandez-Bellot, E., Cullin, C., Melki, R. J. Biol. Chem. (1999) [Pubmed]
  4. A combined algorithm for genome-wide prediction of protein function. Marcotte, E.M., Pellegrini, M., Thompson, M.J., Yeates, T.O., Eisenberg, D. Nature (1999) [Pubmed]
  5. Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism. Lundmark, K., Westermark, G.T., Olsén, A., Westermark, P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion. DePace, A.H., Santoso, A., Hillner, P., Weissman, J.S. Cell (1998) [Pubmed]
  7. A potential positive feedback loop controlling CLN1 and CLN2 gene expression at the start of the yeast cell cycle. Cross, F.R., Tinkelenberg, A.H. Cell (1991) [Pubmed]
  8. Evidence for the prion hypothesis: induction of the yeast [PSI+] factor by in vitro- converted Sup35 protein. Sparrer, H.E., Santoso, A., Szoka, F.C., Weissman, J.S. Science (2000) [Pubmed]
  9. Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone ssb in formation, stability, and toxicity of the [PSI] prion. Chernoff, Y.O., Newnam, G.P., Kumar, J., Allen, K., Zink, A.D. Mol. Cell. Biol. (1999) [Pubmed]
  10. Prion protein gene polymorphisms in Saccharomyces cerevisiae. Resende, C.G., Outeiro, T.F., Sands, L., Lindquist, S., Tuite, M.F. Mol. Microbiol. (2003) [Pubmed]
  11. Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. Derkatch, I.L., Chernoff, Y.O., Kushnirov, V.V., Inge-Vechtomov, S.G., Liebman, S.W. Genetics (1996) [Pubmed]
  12. [PSI] and [URE3] as yeast prions. Wickner, R.B., Masison, D.C., Edskes, H.K. Yeast (1995) [Pubmed]
  13. Guanidine reduces stop codon read-through caused by missense mutations in SUP35 or SUP45. Bradley, M.E., Bagriantsev, S., Vishveshwara, N., Liebman, S.W. Yeast (2003) [Pubmed]
  14. The dominant PNM2- mutation which eliminates the psi factor of Saccharomyces cerevisiae is the result of a missense mutation in the SUP35 gene. Doel, S.M., McCready, S.J., Nierras, C.R., Cox, B.S. Genetics (1994) [Pubmed]
  15. Sensitivity of sup35 and sup45 suppressor mutants in Saccharomyces cerevisiae to the anti-microtubule drug benomyl. Tikhomirova, V.L., Inge-Vechtomov, S.G. Curr. Genet. (1996) [Pubmed]
  16. Modulation of prion formation, aggregation, and toxicity by the actin cytoskeleton in yeast. Ganusova, E.E., Ozolins, L.N., Bhagat, S., Newnam, G.P., Wegrzyn, R.D., Sherman, M.Y., Chernoff, Y.O. Mol. Cell. Biol. (2006) [Pubmed]
  17. Ribosome-bound EF-1 alpha-like protein of yeast Saccharomyces cerevisiae. Didichenko, S.A., Ter-Avanesyan, M.D., Smirnov, V.N. Eur. J. Biochem. (1991) [Pubmed]
  18. Altered 40 S ribosomal subunits in omnipotent suppressors of yeast. Eustice, D.C., Wakem, L.P., Wilhelm, J.M., Sherman, F. J. Mol. Biol. (1986) [Pubmed]
  19. Genetic study of interactions between the cytoskeletal assembly protein sla1 and prion-forming domain of the release factor Sup35 (eRF3) in Saccharomyces cerevisiae. Bailleul, P.A., Newnam, G.P., Steenbergen, J.N., Chernoff, Y.O. Genetics (1999) [Pubmed]
  20. Prions of yeast as heritable amyloidoses. Wickner, R.B., Taylor, K.L., Edskes, H.K., Maddelein, M.L., Moriyama, H., Roberts, B.T. J. Struct. Biol. (2000) [Pubmed]
  21. A model for Ure2p prion filaments and other amyloids: the parallel superpleated beta-structure. Kajava, A.V., Baxa, U., Wickner, R.B., Steven, A.C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  22. Interaction between yeast Sup45p (eRF1) and Sup35p (eRF3) polypeptide chain release factors: implications for prion-dependent regulation. Paushkin, S.V., Kushnirov, V.V., Smirnov, V.N., Ter-Avanesyan, M.D. Mol. Cell. Biol. (1997) [Pubmed]
  23. Hsp104 binds to yeast Sup35 prion fiber but needs other factor(s) to sever it. Inoue, Y., Taguchi, H., Kishimoto, A., Yoshida, M. J. Biol. Chem. (2004) [Pubmed]
  24. Propagation of the yeast prion-like [psi+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor. Paushkin, S.V., Kushnirov, V.V., Smirnov, V.N., Ter-Avanesyan, M.D. EMBO J. (1996) [Pubmed]
  25. Overexpression of the SUP45 gene encoding a Sup35p-binding protein inhibits the induction of the de novo appearance of the [PSI+] prion. Derkatch, I.L., Bradley, M.E., Liebman, S.W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. Poly(A)-binding protein acts in translation termination via eukaryotic release factor 3 interaction and does not influence [PSI(+)] propagation. Cosson, B., Couturier, A., Chabelskaya, S., Kiktev, D., Inge-Vechtomov, S., Philippe, M., Zhouravleva, G. Mol. Cell. Biol. (2002) [Pubmed]
  27. Molecular chaperones and the assembly of the prion Sup35p, an in vitro study. Krzewska, J., Melki, R. EMBO J. (2006) [Pubmed]
  28. Curing of yeast [PSI+] prion by guanidine inactivation of Hsp104 does not require cell division. Wu, Y.X., Greene, L.E., Masison, D.C., Eisenberg, E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  29. The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. Stansfield, I., Jones, K.M., Kushnirov, V.V., Dagkesamanskaya, A.R., Poznyakovski, A.I., Paushkin, S.V., Nierras, C.R., Cox, B.S., Ter-Avanesyan, M.D., Tuite, M.F. EMBO J. (1995) [Pubmed]
  30. The yeast non-Mendelian factor [ETA+] is a variant of [PSI+], a prion-like form of release factor eRF3. Zhou, P., Derkatch, I.L., Uptain, S.M., Patino, M.M., Lindquist, S., Liebman, S.W. EMBO J. (1999) [Pubmed]
  31. The decapping enzyme Dcp1 participates in translation termination through its interaction with the release factor eRF3 in budding yeast. Kofuji, S., Sakuno, T., Takahashi, S., Araki, Y., Doi, Y., Hoshino, S., Katada, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  32. A faux 3'-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Amrani, N., Ganesan, R., Kervestin, S., Mangus, D.A., Ghosh, S., Jacobson, A. Nature (2004) [Pubmed]
  33. Is there a human [psi]? Jean-Jean, O., Le Goff, X., Philippe, M. C. R. Acad. Sci. III, Sci. Vie (1996) [Pubmed]
  34. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Patino, M.M., Liu, J.J., Glover, J.R., Lindquist, S. Science (1996) [Pubmed]
  35. The assembly of amyloidogenic yeast sup35 as assessed by scanning (atomic) force microscopy: an analogy to linear colloidal aggregation? Xu, S., Bevis, B., Arnsdorf, M.F. Biophys. J. (2001) [Pubmed]
  36. Absence of structural homology between sup1 and sup2 genes of yeast Saccharomyces cerevisiae and identification of their transcripts. Surguchov, A.P., Telkov, M.V., Smirnov, V.N. FEBS Lett. (1986) [Pubmed]
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