Disease relevance of TFS1

• Moreover, Tfs1p belongs to the phosphatidylethanolamine-binding protein (PEBP) family, one member of which is RKIP, a kinase and serine protease inhibitor and a metastasis inhibitor in prostate cancer [1].
• Recently, significant sequence homologies were found with an antigen from Onchocerca volvulus, a fruit fly odorant-binding protein and the yeast protein TFS1 which is a dosage-dependent suppressor of CDC25 mutations [2].

High impact information on TFS1

• The molecular analysis of the NSP1 protein points to a two domain model: a nonessential domain (the first 603 amino acids) composed of repetitive sequences common to other nuclear proteins and an essential, carboxy-terminal domain (residues 604-823) mediating the vital function of NSP1 [3].
• The affinity-purified antibody against the yeast NSP1 protein stained the nucleus and centrosomes of mammalian MDCK (Madin Darby canine kidney) cells in indirect immunofluorescence [4].
• The N-terminal acetylation status of Tfs1p, Act1p, and Rnr4p in both wild type and nat3Delta was confirmed by tandem mass spectrometry [5].
• The involvement of Nat3p and Tfs1p in PKA signaling was supported by caffeine growth inhibition studies [5].
• We conclude that the NatB-dependent acetylation of Tfs1p appears to be essential for its inhibitory activity on CPY as well its role in regulating the PKA pathway [5].

Biological context of TFS1

• The DNA sequence of TFS1 contains a single long open reading frame encoding a 219 amino acid polypeptide that is similar in sequence to two mammalian brain proteins [6].
• TFS1 maps to a previously undefined locus on chromosome XII between RDN1 and CDC42 [6].
• In this work, the results of (i) a two-hybrid screen of a yeast genomic library, (ii) glutathione S-transferase pulldown experiments, (iii) multicopy suppressor tests of cdc25-1 mutants, and (iv) stress resistance tests to evaluate the activation level of Ras demonstrate that Tfs1p interacts with and inhibits Ira2p [1].
• The multiple site binding of carboxypeptidase Y inhibitor (IC) to the cognate proteinase. Implications for the biological roles of the phosphatidylethanolamine-binding protein [7].
• A haploid Sz. pombe strain with tfs1 deleted from the genome is viable [8].

Anatomical context of TFS1

• Consistent with a cytoplasmic localization, Ic is soluble and contains no sequences which could serve as potential signals for transport into the endoplasmic reticulum [9].
• Only one form of active carboxypeptidase Y is found to be present in the proteolytically activated extracts, i.e., no polypeptide fragments of carboxypeptidase Y-inhibitor remain bound to the enzyme after it has been activated by proteinase B. In vacuoles prepared from spheroplasts no inactive carboxypeptidase Y can be detected [10].

Associations of TFS1 with chemical compounds

• The stress-induced carboxypeptidase Y (CPY) inhibitor and phosphatidylethanolamine-binding protein family member Tfs1p was identified as a novel NatB substrate [5].
• Furthermore it was found that unacetylated Tfs1p expressed in nat3Delta showed an approximately 100-fold decrease in CPY inhibition compared with the acetylated form, indicating that the N-terminal acetyl group is essential for CPY inhibition by Tfs1p [5].
• Considering their homology to Ic, it is tempting to speculate that they may also be inhibitors of serine carboxypeptidases [9].
• However, deletion of tfs1 results in slow growth and increased sensitivity to the drug 6-azauracil, a phenotype similar to that of a S. cerevisiae strain deleted for the gene encoding TFIIS [8].

Regulatory relationships of TFS1

• The ability of TFS1 to suppress cdc25 is allele specific: the temperature-sensitive cdc25-1 mutation is suppressed efficiently but the cdc25-5 mutation and two disruption mutations are only partially suppressed [6].
• At pH 5, the carboxypeptidase Y-inhibitor complex is activated both by proteinase A (EC 3.4.23.6) and B. Yeast proteinases are activated in a crude extract by incubation at pH 5 [3] [10].

Other interactions of TFS1

• TFS1: a suppressor of cdc25 mutations in Saccharomyces cerevisiae [6].
• In this work, we describe Tfs1p, the first physiological inhibitor of a Ras GAP, Ira2p, in Saccharomyces cerevisiae [1].

Analytical, diagnostic and therapeutic context of TFS1

• Sequence analysis of the cloned NSP1 locus suggests that the NSP1 product contains 269 amino acids and has a membrane-spanning domain at its carboxyl terminus [11].

References