ANALYSIS OF THE LIGAND-BINDING SITE IN FAS (CD95) BY SITE-DIRECTED MUTAGENESIS AND COMPARISON WITH TNFR AND CD40

Fas and its ligand (FasL) are members of the tumor necrosis factor rec eptor (TNFR) and tumor necrosis factor (TNF) superfamilies, respective ly, Fas-FasL interactions trigger controlled cell death (apoptosis) in the immune system and thus play a key role in the regulation of immun e responses, Structural details of the Fas-Fas ligand interaction are currently unknown, Previously, six Fas residues were identified by mut agenesis as important for ligand binding. We have now extended our mut agenesis analysis and identified additional residues which contribute to the Fas-FasL interaction. Candidate and control residues were selec ted based on a molecular model of the Fas extracellular region. Althou gh residues in all three extracellular domains were identified to cont ribute to binding, the Fas-FasL interaction is centered on the second TNFR-like domain. Important residues were compared to critical positio ns in TNFR and CD40, another member of the TNFR family.