Identification of the ligand binding site in Fas (CD95) and analysis of Fas-ligand interactions

Fas (CD95), a member of the tumor necrosis factor receptor superfamily, and its ligand (FasL), a tumor necrosis factor-like protein, are intensely stu died because their interaction on the cell surface is critical for the indu ction of programmed cell death (apoptosis) and the regulation of immune res ponses. The structure and specificity of the extracellular binding domains of Fas and its ligand were studied, in different laboratories, by combining molecular modeling, mutagenesis, and a variety of binding and functional e xperiments. Residues critical for the receptor-ligand interaction were iden tified and, in the absence of experimentally determined structures, binding sites and details of the Fas-ligand interactions were predicted. These stu dies provide an instructive example for the close combination of prediction and experiment and illustrate how insights into the structure and binding characteristics of Fas and its ligand were gradually refined. Discussed met hodological aspects are representative of structure-function studies on ext racellular domains of other single-path transmembrane proteins. Proteins 19 99;35:475-482, (C) 1999 Wiley-Liss, Inc.