TFS1/YLR178C Summary Help

Standard Name TFS1 1, 2
Systematic Name YLR178C
Alias DKA1
Feature Type ORF, Verified
Description Inhibitor of carboxypeptidase Y (Prc1p), and Ras GAP (Ira2p); phosphatidylethanolamine-binding protein (PEBP) family member and ortholog of hPEBP1/RKIP, a natural metastasis suppressor; targets to vacuolar membranes during stationary phase; acetylated by NatB N-terminal acetyltransferase; protein abundance increases in response to DNA replication stress (3, 4, 5, 6, 7, 8, 9 and see Summary Paragraph)
Name Description cdc Twenty-Five Suppressor 1
Chromosomal Location
ChrXII:513821 to 513162 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Gbrowse
Genetic position: 124 cM
Gene Ontology Annotations All TFS1 GO evidence and references
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 15 genes
Resources
Classical genetics
null
overexpression
Large-scale survey
null
unspecified
Resources
40 total interaction(s) for 29 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 17
  • Affinity Capture-RNA: 3
  • Affinity Capture-Western: 4
  • Biochemical Activity: 1
  • Reconstituted Complex: 3
  • Two-hybrid: 2

Genetic Interactions
  • Dosage Rescue: 3
  • Negative Genetic: 3
  • Positive Genetic: 2
  • Synthetic Rescue: 2

Resources
Expression Summary
histogram
Resources
Length (a.a.) 219
Molecular Weight (Da) 24,357
Isoelectric Point (pI) 6.52
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXII:513821 to 513162 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
SGD ORF map
Genetic position: 124 cM
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..660 513821..513162 2011-02-03 1996-07-31
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) | UniProtKB
Primary SGDIDS000004168
SUMMARY PARAGRAPH for TFS1

TFS1 encodes an anionic phospholipid binding protein with roles in regulation of the protein kinase A (PKA) signaling pathway as well as inhibition of the vacuolar protease CPY (carboxypeptidase Y, encoded by Prc1p; 6, 5). TFS1 was first identified as an allele-specific, high copy suppressor of the cdc25-1 mutation (10, 1). Suppression was found to be mediated through interaction with and inhibition of the GTPase-activating protein Ira2p, a negative regulator of RAS function (4). Loss of the negative regulation of RAS protein allows the cAMP/PKA pathway to be activated, which in turn controls cell growth and metabolism. Tfs1p was independently isolated as a 25 kDa inhibitor of vacuolar carboxypeptidase Y (3). The protein was purified and shown to undergo N-terminal acetylation that is mediated by NatB (Nat3p and Mdm20p) and is required for its role in CPY inhibition (3, 5). Purified Tfs1p is a monomer that has multiple binding sites for CPY (11, 12). CPY binding prevents interaction of Tfs1p with phospholipid membranes (6). In vitro assays indicate that Tfs1p has affinity for anionic phospholipids, particularly phosphatidylserine, PtdIns(3)P, PtdIns(3,4)P2, and PtdIns(3,4,5)P3 (6). During log phase growth, Tfs1p is found in the cytoplasm; it is relocalized to the vacuole in stationary phase (6, 13).

TFS1 is highly transcribed in stationary phase (13). Transcription is also modulated by environmental stress; the TFS1 promoter contains two stress-responsive (STRE) elements, and TFS1 expression is elevated in response to oxidative stress, diauxic shift, or heat shock (14, 15, 16). Null mutations in TFS1 confer increased resistance to heat shock, as well as increased CPY activity (due to loss of inhibition mediated by Tfs1p); overexpression confers decreased resistance to heat shock (4, 5). In addition, null mutations suppress sensitivity to caffeine, which inhibits growth by increasing cAMP concentration and consequently PKA activity (5).

TFS1 is a member of a family of proteins termed PEBP (phosphatidylethanolamine-binding protein), which includes mammalian PEBP1, a protein that is found in reproductive and brain tissue, and Arabidopsis floral regulators FL and TFL1 (17; reviewed in 18). PEBPs appear to play roles in different protein inhibition activities (reviewed in 5). Notably, PEBP1 is involved in suppressing metastasis in prostate cancer (19). Members of this family contain a central beta-sheet structure and a small surface anion-binding cavity (reviewed in 6). Mutant analysis indicates that both this cavity and the N-terminal region of Tfs1p are necessary for interaction of Tfs1p and Ira2p (4, 20).

Last updated: 2009-08-24 Contact SGD

References cited on this page View Complete Literature Guide for TFS1
1) Robinson LC and Tatchell K  (1991) TFS1: a suppressor of cdc25 mutations in Saccharomyces cerevisiae. Mol Gen Genet 230(1-2):241-50
2) Robinson, L.C. and Tatchell, K.  (1989) Personal Communication, Mortimer Map Edition 10
3) Bruun AW, et al.  (1998) A high-affinity inhibitor of yeast carboxypeptidase Y is encoded by TFS1 and shows homology to a family of lipid binding proteins. Biochemistry 37(10):3351-7
4) Chautard H, et al.  (2004) Tfs1p, a member of the PEBP family, inhibits the Ira2p but not the Ira1p Ras GTPase-activating protein in Saccharomyces cerevisiae. Eukaryot Cell 3(2):459-70
5) Caesar R and Blomberg A  (2004) The stress-induced Tfs1p requires NatB-mediated acetylation to inhibit carboxypeptidase Y and to regulate the protein kinase A pathway. J Biol Chem 279(37):38532-43
6) Mima J, et al.  (2006) Specific membrane binding of the carboxypeptidase Y inhibitor I(C), a phosphatidylethanolamine-binding protein family member. FEBS J 273(23):5374-83
7) Gombault A, et al.  (2009) A phenotypic study of TFS1 mutants differentially altered in the inhibition of Ira2p or CPY. FEMS Yeast Res 9(6):867-74
8) Beaufour M, et al.  (2012) Interaction proteomics suggests a new role for the tfs1 protein in yeast. J Proteome Res 11(6):3211-8
9) Tkach JM, et al.  (2012) Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. Nat Cell Biol 14(9):966-76
10) Tripp ML, et al.  (1989) Cloning and characterization of NSP1, a locus encoding a component of a CDC25-dependent, nutrient-responsive pathway in Saccharomyces cerevisiae. Mol Microbiol 3(10):1319-27
11) Mima J, et al.  (2002) Overexpression and functional characterization of a serine carboxypeptidase inhibitor (I(C)) from Saccharomyces cerevisiae. J Biochem (Tokyo) 132(6):967-73
12) Mima J, et al.  (2003) The multiple site binding of carboxypeptidase Y inhibitor (IC) to the cognate proteinase. Implications for the biological roles of the phosphatidylethanolamine-binding protein. J Biol Chem 278(32):29792-8
13) Fukada H, et al.  (2007) Biochemical Analysis of the Yeast Proteinase Inhibitor (I(C)) Homolog I(C)h and Its Comparison with I(C). Biosci Biotechnol Biochem 71(2):472-80
14) Boy-Marcotte E, et al.  (1999) The heat shock response in yeast: differential regulations and contributions of the Msn2p/Msn4p and Hsf1p regulons. Mol Microbiol 33(2):274-83
15) Boy-Marcotte E, et al.  (1998) Msn2p and Msn4p control a large number of genes induced at the diauxic transition which are repressed by cyclic AMP in Saccharomyces cerevisiae. J Bacteriol 180(5):1044-52
16) Godon C, et al.  (1998) The H2O2 stimulon in Saccharomyces cerevisiae. J Biol Chem 273(35):22480-9
17) Kobayashi Y, et al.  (1999) A pair of related genes with antagonistic roles in mediating flowering signals. Science 286(5446):1960-2
18) Schoentgen F and Jolles P  (1995) From structure to function: possible biological roles of a new widespread protein family binding hydrophobic ligands and displaying a nucleotide binding site. FEBS Lett 369(1):22-6
19) Fu Z, et al.  (2003) Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 95(12):878-89
20) Gombault A, et al.  (2007) Molecular basis of the tfs1/ira2 interaction: a combined protein engineering and molecular modelling study. J Mol Biol 374(3):604-17