# Sup35p
**Sup35p** is the essential translation termination factor eRF3 of the budding yeast *Saccharomyces cerevisiae*, encoded by the nuclear gene **SUP35**, and is best known as the protein whose self-propagating prion conformation produces the non-Mendelian genetic element [PSI+][1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/). In its normal soluble state, Sup35p works with the release factor eRF1 (Sup45p) to recognize stop codons and release the finished polypeptide from the ribosome; in its prion state, most Sup35p molecules aggregate into amyloid fibers, termination becomes inefficient, and cells show increased readthrough of nonsense codons[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/).
| Key fact | Detail |
|---|---|
| Identity | Yeast eRF3, the GTP-dependent class II release factor; product of the SUP35 gene; essential for viability[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC394485/?page=1) |
| Prion element | [PSI+], discovered by Brian Cox in 1965 as a nonchromosomal element that modulates nonsense suppression[4](https://journals.asm.org/doi/abs/10.1128/mmbr.00041-14) • [5](https://pubmed.ncbi.nlm.nih.gov/16757178/) |
| Prion mechanism | Self-propagating amyloid aggregates of Sup35p sequester the soluble protein, raising readthrough of stop codons[6](https://pubmed.ncbi.nlm.nih.gov/10915616/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/) |
| Domain layout | N-terminal glutamine/asparagine-rich prion-forming domain, charged middle (M) domain, C-terminal GTPase domain carrying the essential termination function[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC4024371/) • [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/) |
| Minimal prion domain | Residues 1 to 114 (Sup35N) suffice to propagate the original [PSI+]; residues 1 to 61 suffice for several variants[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4402965/) |
| Propagation factor | [PSI+] propagation depends on the heat shock protein Hsp104[9](https://academic.oup.com/femspd/article/73/9/ftv087/2467603) |
| Third state | Under short heat or pH stress, Sup35p reversibly assembles into biomolecular condensates by phase separation[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/) |
## Discovery of the [PSI+] factor
The element now called [PSI+] was found in 1965 by Brian Cox, then at the [University of Oxford](https://www.edgepedia.org/university-of-oxford), during a genetic analysis of nonsense suppressors in *S. cerevisiae*. Cox was following the inheritance of the dominant nonsense suppressor SUQ5 (also called SUP16), using suppression of the ochre ade2-1 allele as a marker: cells carrying ade2-1 normally form red colonies and require adenine, but suppression by SUQ5 yields adenine-prototrophic white colonies. In some strains the degree of suppression behaved as a nonchromosomal, non-Mendelian factor, which Cox named ψ (psi)[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/) • [4](https://journals.asm.org/doi/abs/10.1128/mmbr.00041-14). Soon afterward, François Lacroute found a second nonchromosomal element, [URE3], which allowed a ura2 mutant to take up ureidosuccinate[4](https://journals.asm.org/doi/abs/10.1128/mmbr.00041-14).
For decades the molecular nature of the ψ factor remained unexplained. In 1994 [Reed Wickner](https://www.edgepedia.org/reed-b-wickner) proposed that such elements could be accounted for by a prion model, in which the determinant is an alternate, self-perpetuating conformation of a protein rather than a nucleic acid, and suggested that [PSI+] is the prion form of Sup35p and [URE3] the prion form of Ure2p[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/) • [5](https://pubmed.ncbi.nlm.nih.gov/16757178/).
## Identification of Sup35p as the prion protein
Three independent genetic findings pointed to the SUP35 product as the prion protein of [PSI+][2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/):
1. Mutations in SUP35 can make cells unable to maintain the [PSI+] determinant, converting them to [psi−].
2. Mutations in SUP35, originally known as sal3 mutants, give the same phenotype as cells carrying [PSI+].
3. Overexpression of SUP35 leads to the de novo appearance of [PSI+] strains.
Within three years of Wickner's paper, several independent studies supplied genetic and biochemical support that the [PSI+] determinant is the prion form of Sup35p[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/). The decisive test came from protein transformation: purified, bacterially produced Sup35p converted to its prion conformation in vitro and introduced into living [psi−] yeast by a liposome protocol triggered a high rate of stable conversion to [PSI+], even at substoichiometric quantities[6](https://pubmed.ncbi.nlm.nih.gov/10915616/). Earlier, King and Wüthrich had shown that a Sup35p prion domain can form amyloid in vitro, and Glover and colleagues showed that extracts of [PSI+] cells can seed amyloid formation by the Sup35NM region[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3340228/).
## Structure and domains
Sup35p has three functionally distinct regions. The C-terminal domain carries the essential termination activity: it contains a GTPase fold, hydrolyzes GTP, and interacts with Sup45p (eRF1), the class I factor that recognizes all three stop codons; GTP hydrolysis by Sup35p provides the energy for dissociation of the termination complex and release of the new polypeptide[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC394485/?page=1). This C-terminal region is highly conserved among eRF3 proteins from yeasts, frogs, and humans, and shows significant similarity to elongation factor eEF1A and bacterial RF3[11](https://journals.asm.org/doi/10.1128/mmbr.62.4.1492-1553.1998).
The N-terminal region is a glutamine- and asparagine-rich prion-forming domain, dispensable for termination but responsible for conversion into the aggregated, functionally inactive prion form; it includes a repeat region with degenerate tandem repeats that stabilize intermolecular contacts within aggregates[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC4024371/) • [1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/) • [12](https://link.springer.com/article/10.1186/1471-2199-7-34). Between these lies the highly charged M domain, required for neither prion formation nor the normal cellular function, but which helps stabilize [PSI+][7](https://pmc.ncbi.nlm.nih.gov/articles/PMC4024371/). The [N-terminus](https://www.edgepedia.org/n-terminus) also binds the yeast poly(A)-binding protein Pab1p, an interaction proposed to help position the eRF1/eRF3 complex near stop codons[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/).
## The prion state and its phenotype
In [PSI+] cells, Sup35p in its aggregated prion conformation is largely unavailable for termination, so ribosomes read through stop codons more often. On reporter alleles such as ade1-14, this readthrough suppresses a premature stop codon: [psi−] strains form red colonies and cannot grow without adenine, while [PSI+] strains appear pink or white and grow on adenine-free medium[13](https://journals.plos.org/plosbiology/article?id=10.1371%2Fjournal.pbio.0020086). Multiple [PSI+] "strains" or variants exist, analogous to alleles of nucleic-acid inheritance; weak variants show weak nonsense suppression and pink coloration on rich medium[14](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/biot.200500001). [In vitro](https://www.edgepedia.org/in-vitro)-generated Sup35 amyloid can promote the formation of such phenotypically distinct variants[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964859/).
Propagation of [PSI+] in dividing cells depends on the molecular chaperone Hsp104, a dependence first found by Sue Liebman's group and colleagues in 1995, which launched the structural biochemistry of yeast prions[9](https://academic.oup.com/femspd/article/73/9/ftv087/2467603). The prion domains of Sup35p and Ure2p are rich in glutamine and asparagine and poor in charged residues, a property shared by most, though not all, yeast prion proteins[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC4402965/).
## Sup35p among yeast prions and related proteins
[PSI+] is one of three native yeast prions studied intensively, alongside [URE3] (prion of Ure2p) and [PIN+] (prion of Rnq1p); the fungus *Podospora anserina* has the analogous [Het-s] element based on the HET-s protein[4](https://journals.asm.org/doi/abs/10.1128/mmbr.00041-14) • [16](https://www.sciencedirect.com/science/article/pii/S0076687999090436). The prion domains of Ure2p and Sup35p have nonprion cellular functions, which explains their retention in evolution despite the detrimental effects of prion formation[4](https://journals.asm.org/doi/abs/10.1128/mmbr.00041-14). Sup35p homologs are found in various yeast species, and eRF3 exists across eukaryotes, but many orthologs, such as the Dictyostelium ERF3 protein, lack the glutamine/asparagine-rich domain needed for prion formation[17](https://journals.asm.org/doi/pdf/10.1128/spectrum.01607-24).
## Three states of one protein
Work on Sup35p has shown that a single protein can occupy three distinct states with different biological meanings. As soluble eRF3 it performs the essential termination of translation; under short-term heat or pH stress it undergoes reversible phase separation into biomolecular condensates, localized areas of high protein concentration; and, rarely, it misfolds into self-perpetuating infectious amyloid propagated for many generations as [PSI+][1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/). Because a protein-based inheritance mechanism can have a beneficial impact on a cell's fitness, yeast prions are studied not only as models relevant to mammalian prion biology but as heritable systems in their own right[5](https://pubmed.ncbi.nlm.nih.gov/16757178/).
## References
1. [The Three Faces of Sup35, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7373163/)
2. [Tuite MF, Cox BS. The Genetic Control of the Formation and Propagation of the [PSI+] Prion of Yeast, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2634449/)
3. [Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC394485/?page=1)
4. [Wickner RB et al. Yeast Prions: Structure, Biology, and Prion-Handling Systems, Microbiology and Molecular Biology Reviews](https://journals.asm.org/doi/abs/10.1128/mmbr.00041-14)
5. [Tuite MF, Cox BS. The [PSI+] prion of yeast: a problem of inheritance, Methods (2006)](https://pubmed.ncbi.nlm.nih.gov/16757178/)
6. [Sparrer HE et al. Evidence for the prion hypothesis: induction of the yeast [PSI+] factor by in vitro-converted Sup35 protein, Science (2000)](https://pubmed.ncbi.nlm.nih.gov/10915616/)
7. [Yeast prions and human prion-like proteins: sequence features and prediction methods, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4024371/)
8. [Yeast Prions: Structure, Biology, and Prion-Handling Systems, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4402965/)
9. [A brief history of prions, Pathogens and Disease, Oxford Academic](https://academic.oup.com/femspd/article/73/9/ftv087/2467603)
10. [Discovering Protein-based Inheritance through Yeast Genetics, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3340228/)
11. [Posttranscriptional Control of Gene Expression in Yeast, Microbiology and Molecular Biology Reviews](https://journals.asm.org/doi/10.1128/mmbr.62.4.1492-1553.1998)
12. [N-terminal region of Saccharomyces cerevisiae eRF3 is essential for the functioning of the eRF1/eRF3 complex beyond translation termination, BMC Molecular Biology](https://link.springer.com/article/10.1186/1471-2199-7-34)
13. [Dissection and Design of Yeast Prions, PLOS Biology](https://journals.plos.org/plosbiology/article?id=10.1371%2Fjournal.pbio.0020086)
14. [Using budding yeast to screen for anti-prion drugs, Biotechnology Journal](https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/biot.200500001)
15. [[PSI+] turns 50, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964859/)
16. [Yeast prion [Ψ+] and its determinant, sup35p, Methods in Enzymology](https://www.sciencedirect.com/science/article/pii/S0076687999090436)
17. [Acute stress and multicellular development alter the solubility of the Dictyostelium Sup35 ortholog ERF3, ASM Spectrum](https://journals.asm.org/doi/pdf/10.1128/spectrum.01607-24)
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*Topic: Encyclopedia › Life and health › Biological foundations › RNA and gene regulation › RNA processing, modification, and translation › Transfer RNA, ribosomal RNA, and translation › Translation factors › Termination and ribosome recycling factors*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license