URE2/YNL229C Summary Help

Standard Name URE2 1
Systematic Name YNL229C
Feature Type ORF, Verified
Description Nitrogen catabolite repression transcriptional regulator; inhibits GLN3 transcription in good nitrogen source; role in sequestering Gln3p and Gat1p to the cytoplasm; has glutathione peroxidase activity and can mutate to acquire GST activity; altered form creates [URE3] prion (2, 3, 4, 5, 6, 7 and see Summary Paragraph)
Also known as: [URE3] 4
Name Description UREidosuccinate transport 1
Chromosomal Location
ChrXIV:220201 to 219137 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Genetic position: -142 cM
Gene Ontology Annotations All URE2 GO evidence and references
  View Computational GO annotations for URE2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Targets 18 genes
Regulators 4 genes
Classical genetics
Large-scale survey
379 total interaction(s) for 294 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 14
  • Affinity Capture-RNA: 5
  • Affinity Capture-Western: 5
  • Co-crystal Structure: 5
  • PCA: 13
  • Reconstituted Complex: 21
  • Two-hybrid: 24

Genetic Interactions
  • Dosage Rescue: 5
  • Negative Genetic: 205
  • Phenotypic Enhancement: 12
  • Phenotypic Suppression: 25
  • Positive Genetic: 20
  • Synthetic Growth Defect: 14
  • Synthetic Lethality: 6
  • Synthetic Rescue: 5

Expression Summary
Length (a.a.) 354
Molecular Weight (Da) 40,271
Isoelectric Point (pI) 6.45
Phosphorylation PhosphoGRID | PhosphoPep Database
sequence information
ChrXIV:220201 to 219137 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Genetic position: -142 cM
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Most Recent Updates
Coordinates Sequence
CDS 1..1065 220201..219137 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000005173

URE2 encodes a bifunctional protein that is involved in both nitrogen catabolite repression (8) and oxidative stress response (9, 10). When optimal sources of nitrogen are available, Ure2p acts as a transcriptional corepressor and downregulates the expression of many genes involved in nitrogen utilization by inhibiting the GATA transcriptional activators Gln3p and Gat1p (2, 11). Ure2p, which localizes to the cytosol, binds to the phosphorylated forms of Gln3p and Gat1p and prevents them from entering the nucleus (12, 13, 11). URE2 may have an additional role in protecting the cell from oxidative stress. Ure2p, which forms a homodimer by dimerizing through its C-terminal region (14), binds glutathione with high affinity (15, 16) and has been shown to exhibit glutathione peroxidase activity in vitro (5). The crystal structure of Ure2p also shows that it has structural similarity to glutathione S-transferases (8, 17).

Ure2p enzyme activity is repressed by the pleiotropic regulatory protein Mks1p (18). URE2 does not appear to be regulated (8), but the URE2 mRNA contains an internal ribosome entry site (IRES) from which translation is repressed by YGR054W, the yeast homolog of the mammalian protein Eukaryotic Initiation Factor 2A (19). IRES-mediated translation leads to an N-terminally truncated form of the protein that retains regulatory activity but is unable to drive prion formation (see below) (20).

S. cerevisiae cells lacking functional Ure2p no longer respond to NCR and can thus utilize poor nitrogen sources even in the presence of optimal ones (2, 8). This condition results in improved alcoholic fermentation of fruit juices and grape musts (21). ure2 mutant strains are also hypersensitive to growth inhibition by rapamycin (9) and to the toxic effects of many oxidative agents and heavy metals (22). However, ure2 mutations do lead to improved ion tolerance in calcineurin cnb1 single and cna1 cmp2 double mutants (23).

[URE3] is a yeast prion formed by the autocatalytic conversion of Ure2p into infectious, protease-resistant, amyloid fibrils (4). The Ure2p prion domain spans amino acids 1-89 and is rich in asparagines and glutamines (24, 8), and it has been shown that [URE3] formation is driven primarily by prion domain amino acid composition as opposed to primary sequence (25). The N-terminal prion domain polymerizes to form an amyloid filament backbone surrounded by the C-terminal nitrogen regulatory domains (26). The regulatory domains retain their native conformation but are sterically inactivated (26).

Conversion of Ure2p to [URE3] can be induced by overexpression of either the full-length Ure2p or just the prion domain (4), 27). However, in cells already infected with [URE3], overexpression of the prion domain can cure the cells (28). Other conditions that either clear or prevent [URE3] generation/propagation include: the presence of glutamate (29), growth in medium containing guanidine (4, 30), overexpression of a Ure2-GFP fusion protein (28), expression of truncated Ure2p from the URE2 mRNA IRES (20), loss of the Ure2p repressor Mks1p (31), overexpression of the HSP70 family member Ssa1p (32), expression of a P395L mutant of Ssa2p (33), loss of the protein chaperon Hsp104p (34), or overproduction of the protein chaperone Ydj1p (34).

Although the Ure2p regulatory domain is evolutionarily conserved across several yeast genera (35), the prion domain is not conserved even among related Saccharomyces species (36). [URE3] is being studied as a model for human amyloid diseases such as Alzheimer's disease, non-insulin-dependent diabetes mellitus, and transmissible spongiform encephalopathy (37) and as a target to screen anti-prion drugs (38).

Last updated: 2005-09-26 Contact SGD

References cited on this page View Complete Literature Guide for URE2
1) Drillien R and Lacroute F  (1972) Ureidosuccinic acid uptake in yeast and some aspects of its regulation. J Bacteriol 109(1):203-8
2) Courchesne WE and Magasanik B  (1988) Regulation of nitrogen assimilation in Saccharomyces cerevisiae: roles of the URE2 and GLN3 genes. J Bacteriol 170(2):708-13
3) Blinder D, et al.  (1996) Interaction of the GATA factor Gln3p with the nitrogen regulator Ure2p in Saccharomyces cerevisiae. J Bacteriol 178(15):4734-6
4) Wickner RB  (1994) [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264(5158):566-9
5) Bai M, et al.  (2004) The yeast prion protein Ure2 shows glutathione peroxidase activity in both native and fibrillar forms. J Biol Chem 279(48):50025-30
6) Zhang ZR, et al.  (2008) "Restoration" of glutathione transferase activity by single-site mutation of the yeast prion protein Ure2. J Mol Biol 384(3):641-51
7) Feller A, et al.  (2013) Alterations in the Ure2 aCap domain elicit different GATA factor responses to rapamycin treatment and nitrogen limitation. J Biol Chem 288(3):1841-55
8) Coschigano PW and Magasanik B  (1991) The URE2 gene product of Saccharomyces cerevisiae plays an important role in the cellular response to the nitrogen source and has homology to glutathione s-transferases. Mol Cell Biol 11(2):822-32
9) Rai R and Cooper TG  (2005) In vivo specificity of Ure2 protection from heavy metal ion and oxidative cellular damage in Saccharomyces cerevisiae. Yeast 22(5):343-58
10) Rai R, et al.  (2003) Ure2, a prion precursor with homology to glutathione S-transferase, protects Saccharomyces cerevisiae cells from heavy metal ion and oxidant toxicity. J Biol Chem 278(15):12826-33
11) Cunningham TS, et al.  (2000) Nitrogen catabolite repression of DAL80 expression depends on the relative levels of Gat1p and Ure2p production in Saccharomyces cerevisiae. J Biol Chem 275(19):14408-14
12) Beck T and Hall MN  (1999) The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402(6762):689-92
13) Cox KH, et al.  (2000) Saccharomyces cerevisiae GATA sequences function as TATA elements during nitrogen catabolite repression and when Gln3p is excluded from the nucleus by overproduction of Ure2p. J Biol Chem 275(23):17611-8
14) Thual C, et al.  (2001) Stability, folding, dimerization, and assembly properties of the yeast prion Ure2p. Biochemistry 40(6):1764-73
15) Bousset L, et al.  (2001) Structure of the globular region of the prion protein Ure2 from the yeast Saccharomyces cerevisiae. Structure 9(1):39-46
16) Bousset L, et al.  (2001) Crystal structures of the yeast prion Ure2p functional region in complex with glutathione and related compounds. Biochemistry 40(45):13564-73
17) Umland TC, et al.  (2001) The crystal structure of the nitrogen regulation fragment of the yeast prion protein Ure2p. Proc Natl Acad Sci U S A 98(4):1459-64
18) Edskes HK, et al.  (1999) Mks1p is a regulator of nitrogen catabolism upstream of Ure2p in Saccharomyces cerevisiae. Genetics 153(2):585-94
19) Komar AA, et al.  (2005) Novel characteristics of the biological properties of the yeast Saccharomyces cerevisiae eukaryotic initiation factor 2A. J Biol Chem 280(16):15601-11
20) Komar AA, et al.  (2003) Internal initiation drives the synthesis of Ure2 protein lacking the prion domain and affects [URE3] propagation in yeast cells. EMBO J 22(5):1199-209
21) Salmon JM and Barre P  (1998) Improvement of nitrogen assimilation and fermentation kinetics under enological conditions by derepression of alternative nitrogen-assimilatory pathways in an industrial Saccharomyces cerevisiae strain. Appl Environ Microbiol 64(10):3831-7
22) Cardenas ME, et al.  (1999) The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev 13(24):3271-9
23) Withee JL, et al.  (1998) Ion tolerance of Saccharomyces cerevisiae lacking the Ca2+/CaM-dependent phosphatase (calcineurin) is improved by mutations in URE2 or PMA1. Genetics 149(2):865-78
24) Maddelein ML and Wickner RB  (1999) Two prion-inducing regions of Ure2p are nonoverlapping. Mol Cell Biol 19(6):4516-24
25) Ross ED, et al.  (2004) Scrambled prion domains form prions and amyloid. Mol Cell Biol 24(16):7206-13
26) Baxa U, et al.  (2002) Mechanism of inactivation on prion conversion of the Saccharomyces cerevisiae Ure2 protein. Proc Natl Acad Sci U S A 99(8):5253-60
27) Masison DC and Wickner RB  (1995) Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells. Science 270(5233):93-5
28) Edskes HK, et al.  (1999) 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 96(4):1498-503
29) Sekito T, et al.  (2002) RTG-dependent mitochondria-to-nucleus signaling is regulated by MKS1 and is linked to formation of yeast prion [URE3]. Mol Biol Cell 13(3):795-804
30) Ripaud L, et al.  (2003) The mechanisms of [URE3] prion elimination demonstrate that large aggregates of Ure2p are dead-end products. EMBO J 22(19):5251-9
31) Edskes HK and Wickner RB  (2000) A protein required for prion generation: [URE3] induction requires the Ras-regulated Mks1 protein. Proc Natl Acad Sci U S A 97(12):6625-9
32) Schwimmer C and Masison DC  (2002) Antagonistic interactions between yeast [PSI(+)] and [URE3] prions and curing of [URE3] by Hsp70 protein chaperone Ssa1p but not by Ssa2p. Mol Cell Biol 22(11):3590-8
33) Tibor Roberts B, et al.  (2004) [URE3] prion propagation is abolished by a mutation of the primary cytosolic Hsp70 of budding yeast. Yeast 21(2):107-17
34) Moriyama H, et al.  (2000) [URE3] prion propagation in Saccharomyces cerevisiae: requirement for chaperone Hsp104 and curing by overexpressed chaperone Ydj1p. Mol Cell Biol 20(23):8916-22
35) Baudin-Baillieu A, et al.  (2003) Conservation of the prion properties of Ure2p through evolution. Mol Biol Cell 14(8):3449-58
36) Talarek N, et al.  (2005) The [URE3] prion is not conserved among Saccharomyces species. Genetics 171(1):23-34
37) Serio TR and Lindquist SL  (2000) Protein-only inheritance in yeast: something to get [PSI+]-ched about. Trends Cell Biol 10(3):98-105
38) Bach S, et al.  (2003) Isolation of drugs active against mammalian prions using a yeast-based screening assay. Nat Biotechnol 21(9):1075-81