FUR4/YBR021W Summary Help

Standard Name FUR4 1
Systematic Name YBR021W
Feature Type ORF, Verified
Description Plasma membrane localized uracil permease; expression is tightly regulated by uracil levels and environmental cues; conformational alterations induced by unfolding or substrate binding result in Rsp5p-mediated ubiquitination and degradation (2, 3, 4, 5 and see Summary Paragraph)
Name Description 5-FlUoRouridine sensitivity 1
Chromosomal Location
ChrII:281443 to 283344 | ORF Map | GBrowse
Gbrowse
Genetic position: 8 cM
Gene Ontology Annotations All FUR4 GO evidence and references
  View Computational GO annotations for FUR4
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
High-throughput
Regulators 5 genes
Resources
Classical genetics
null
Large-scale survey
null
overexpression
repressible
Resources
11 total interaction(s) for 10 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 2
  • Co-localization: 2
  • PCA: 1

Genetic Interactions
  • Dosage Rescue: 1
  • Positive Genetic: 3
  • Synthetic Growth Defect: 1
  • Synthetic Lethality: 1

Resources
Expression Summary
histogram
Resources
Length (a.a.) 633
Molecular Weight (Da) 71,735
Isoelectric Point (pI) 7.86
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrII:281443 to 283344 | ORF Map | GBrowse
SGD ORF map
Genetic position: 8 cM
Last Update Coordinates: 2004-07-16 | Sequence: 1997-01-28
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..1902 281443..283344 2004-07-16 1997-01-28
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | TCDB | UniProtKB
Primary SGDIDS000000225
SUMMARY PARAGRAPH for FUR4

Fur4p is a uracil permease that mediates the uptake of uracil, but does not transport other natural pyrimidines such as cytosine, thymine, or uridine (6, 7). It is localized to lipid microdomains of the plasma membrane that also contain Can1p and Sur7p (8) Fur4p functions as a symporter by actively translocating uracil with the co-transport of protons (9). Since the magnitude of the proton gradient across the plasma membrane influences the rate of uracil uptake by Fur4p, the rate fluctuates with varying ionic conditions (10). The prodrug 5-fluorouracil (5-FU) also enters the cell via Fur4p (6), and the immunosuppressant leflunomide inhibits Fur4p-mediated uracil uptake (11).

Fur4p abundance is an important determinant of intracellular uracil levels, and is therefore under several types of regulation. FUR4 transcription is induced in response to galactose, in a GAL4-dependent manner (12). Fur4p expression is downregulated in the presence of uracil (of either exogenous or catabolic origin) in order to prevent the accumulation of excess intracellular uracil-derived nucleotides (13, 3). FUR4 mRNA is of low abundance and has a high turnover rate, with a half-life of approximately 2 minutes (14, 7). Its abundance is further decreased in response to uracil, probably due to increased degradation (3). Newly synthesized Fur4p is normally delivered to the cell surface via the secretory pathway. However in the presence of excess uracil, newly synthesized Fur4p can be directed to the degradative vacuolar pathway without ever passing through the plasma membrane (13).

Normal degradation of Fur4p occurs through phosphorylation of Fur4p at the plasma membrane, followed by ubiquitination, endocytosis, and finally degradation in the vacuoles. Fur4p is phosphorylated at several serine residues within a well characterized N-terminal PEST sequence (15, 16, 14, 17,), and phosphorylation is dependent on Yck1p and Yck2p, which are serine/threonine kinases (15). Phosphorylation in turn facilitates ubiquitination of Fur4p, which occurs on lysine residues 38 and 41 and is dependent on the Rsp5p ubiquitin-protein ligase (15, 18, 19). Fur4p is then internalized and following endocytosis, is targeted to the vacuole for proteolysis (15, 20, 18). Endocytosis of Fur4p involves End3p and Sla2p functions, and degradation of Fur4p in vacuoles requires the function of Pep4p (21). Cells lacking functional ESCRT complexes (stp22, srn2, vps28, snf8, vps25, vps36, vps20, and vps24 null mutants) accumulate Fur4p at the plasma membrane (22). Uracil also promotes the normal degradation of Fur4p located in the plasma membrane (13, 3, 21). Fur4p is constitutively degraded in exponentially growing cells, and degradation increases in response to adverse conditions such as nutrient starvation, inhibition of protein synthesis, heat shock, or stationary phase (16, 21, 17).

FUR4 is not essential for normal growth of uracil-proficient S. cerevisiae strains (23). fur4 mutants cannot take up uracil and are resistant to 5-fluorouracil (7, 9). Conversely, in cells overexpressing Fur4p, uracil is toxic (24, 13). fur4-[R294A] mutant protein is stabilized compared to wild-type protein during nitrogen starvation or inhibition of protein synthesis (17). FUR4 has similarity to DAL4, FUI1 and THI7, YOR071C, and Schizosaccharomyces pombe fur4 (25, 26, 16, 27, 28). Fur4p can complement the defects of an S. pombe mutant lacking uracil transport activity (29).

Last updated: 2005-12-16 Contact SGD

References cited on this page View Complete Literature Guide for FUR4
1) Jund R and Lacroute F  (1970) Genetic and physiological aspects of resistance to 5-fluoropyrimidines in Saccharomyces cerevisiae. J Bacteriol 102(3):607-15
2) Pinson B, et al.  (1999) Only one of the charged amino acids located in membrane-spanning regions is important for the function of the Saccharomyces cerevisiae uracil permease. Biochem J 339 ( Pt 1)():37-42
3) Seron K, et al.  (1999) Uracil-induced down-regulation of the yeast uracil permease. J Bacteriol 181(6):1793-800
4) Hearn JD, et al.  (2003) The uracil transporter Fur4p associates with lipid rafts. J Biol Chem 278(6):3679-86
5) Keener JM and Babst M  (2013) Quality control and substrate-dependent downregulation of the nutrient transporter Fur4. Traffic 14(4):412-27
6) Kurtz JE, et al.  (1999) New insights into the pyrimidine salvage pathway of Saccharomyces cerevisiae: requirement of six genes for cytidine metabolism. Curr Genet 36(3):130-6
7) Chevallier MR  (1982) Cloning and transcriptional control of a eucaryotic permease gene. Mol Cell Biol 2(8):977-84
8) Malinska K, et al.  (2004) Distribution of Can1p into stable domains reflects lateral protein segregation within the plasma membrane of living S. cerevisiae cells. J Cell Sci 117(Pt 25):6031-41
9) Urban-Grimal D, et al.  (1995) Replacement of Lys by Glu in a transmembrane segment strongly impairs the function of the uracil permease from Saccharomyces cerevisiae. Biochem J 308 ( Pt 3)():847-51
10) Eddy AA and Hopkins P  (1998) Proton stoichiometry of the overexpressed uracil symport of the yeast Saccharomyces cerevisiae. Biochem J 336 ( Pt 1)():125-30
11) Fujimura H  (1998) Growth inhibition of Saccharomyces cerevisiae by the immunosuppressant leflunomide is due to the inhibition of uracil uptake via Fur4p. Mol Gen Genet 260(1):102-7
12) Ren B, et al.  (2000) Genome-wide location and function of DNA binding proteins. Science 290(5500):2306-9
13) Blondel MO, et al.  (2004) Direct sorting of the yeast uracil permease to the endosomal system is controlled by uracil binding and Rsp5p-dependent ubiquitylation. Mol Biol Cell 15(2):883-95
14) Volland C, et al.  (1992) In vivo phosphorylation of the yeast uracil permease. J Biol Chem 267(33):23767-71
15) Marchal C, et al.  (2000) Casein kinase I-dependent phosphorylation within a PEST sequence and ubiquitination at nearby lysines signal endocytosis of yeast uracil permease. J Biol Chem 275(31):23608-14
16) Marchal C, et al.  (1998) A PEST-like sequence mediates phosphorylation and efficient ubiquitination of yeast uracil permease. Mol Cell Biol 18(1):314-21
17) Galan JM, et al.  (1994) The yeast plasma membrane uracil permease is stabilized against stress induced degradation by a point mutation in a cyclin-like "destruction box". Biochem Biophys Res Commun 201(2):769-75
18) Galan J and Haguenauer-Tsapis R  (1997) Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO J 16(19):5847-54
19) Hein C, et al.  (1995) NPl1, an essential yeast gene involved in induced degradation of Gap1 and Fur4 permeases, encodes the Rsp5 ubiquitin-protein ligase. Mol Microbiol 18(1):77-87
20) Galan JM, et al.  (1996) Ubiquitination mediated by the Npi1p/Rsp5p ubiquitin-protein ligase is required for endocytosis of the yeast uracil permease. J Biol Chem 271(18):10946-52
21) Volland C, et al.  (1994) Endocytosis and degradation of the yeast uracil permease under adverse conditions. J Biol Chem 269(13):9833-41
22) Bugnicourt A, et al.  (2004) Antagonistic roles of ESCRT and Vps class C/HOPS complexes in the recycling of yeast membrane proteins. Mol Biol Cell 15(9):4203-14
23) Jund R, et al.  (1988) Primary structure of the uracil transport protein of Saccharomyces cerevisiae. Eur J Biochem 171(1-2):417-24
24) Silve S, et al.  (1991) Membrane insertion of uracil permease, a polytopic yeast plasma membrane protein. Mol Cell Biol 11(2):1114-24
25) de Montigny J, et al.  (1998) The uracil permease of Schizosaccharomyces pombe: a representative of a family of 10 transmembrane helix transporter proteins of yeasts. Yeast 14(11):1051-9
26) De Wergifosse P, et al.  (1994) The sequence of a 22.4 kb DNA fragment from the left arm of yeast chromosome II reveals homologues to bacterial proline synthetase and murine alpha-adaptin, as well as a new permease and a DNA-binding protein. Yeast 10(11):1489-96
27) Wagner R, et al.  (1998) The ORF YBL042 of Saccharomyces cerevisiae encodes a uridine permease. FEMS Microbiol Lett 159(1):69-75
28) Yoo HS, et al.  (1992) The allantoin and uracil permease gene sequences of Saccharomyces cerevisiae are nearly identical. Yeast 8(12):997-1006
29) Chevallier MR and Lacroute F  (1982) Expression of the cloned uracil permease gene of Saccharomyces cerevisiae in a heterologous membrane. EMBO J 1(3):375-7