THE MOLECULAR INTERACTION OF FAS AND FAP-1 - A TRIPEPTIDE BLOCKER OF HUMAN FAS INTERACTION WITH FAP-1 PROMOTES FAS-INDUCED APOPTOSIS

Fas (APO-1/CD95), which isa member of the tumor necrosis factor recept or superfamily, is a cell surface receptor that induces apoptosis. A p rotein tyrosine phosphatase, Fas-associated phosphatase-l (FAP-1), tha t was previously identified as a Fas binding protein interacts with th e C-terminal 15 amino acids of the regulatory domain of the Fas recept or. To identify the minimal region of the Fas C-terminal necessary for binding to FAP-1, we employed an in vitro inhibition assay of Fas/FAP -1 binding using a series of synthetic peptides as well as a screen of random peptide libraries by the yeast two-hybrid system. The results showed that the C-terminal three amino acids (SLV) of human Fas were n ecessary and sufficient for its interaction with the third PDZ (GLGF) domain of FAP-1. Furthermore, the direct cytoplasmic microinjection of this tripeptide (Ac-SLV) resulted in the induction of Fas-mediated ap optosis in a colon cancer cell line that expresses both Fas and FAP-1. Since t(S/T)X(V/L/I) motifs in the C termini of several other recepto rs have been shown to interact with PDZ domain in signal transducing m olecules, this may represent a general motif for protein-protein inter actions with important biological functions.