Analysis of the Ligand Binding Site in Fas (CD95) by Site-Directed Mutagenesis and Comparison with TNFR and CD40

• Published in: Biochemistry (Easton) Vol. 37; no. 11; pp. 3723 - 3726
• Main Authors: Starling, Gary C, Kiener, Peter A, Aruffo, Alejandro, Bajorath, Jürgen
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.03.1998
• Subjects: Amino Acid Sequence; Amino Acid Substitution - genetics; Amino Acids - metabolism; Animals; Antibodies, Monoclonal - metabolism; Binding Sites - genetics; Binding Sites - immunology; CD40 Antigens - genetics; CD40 Antigens - immunology; CD40 Antigens - metabolism; Fas Ligand Protein; fas Receptor - genetics; fas Receptor - immunology; fas Receptor - metabolism; Humans; Ligands; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - metabolism; Structure-Activity Relationship
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi972959d

Fas and its ligand (FasL) are members of the tumor necrosis factor receptor (TNFR) and tumor necrosis factor (TNF) superfamilies, respectively. Fas−FasL interactions trigger controlled cell death (apoptosis) in the immune system and thus play a key role in the regulation of immune responses. Structural details of the Fas−Fas ligand interaction are currently unknown. Previously, six Fas residues were identified by mutagenesis as important for ligand binding. We have now extended our mutagenesis analysis and identified additional residues which contribute to the Fas−FasL interaction. Candidate and control residues were selected based on a molecular model of the Fas extracellular region. Although residues in all three extracellular domains were identified to contribute to binding, the Fas−FasL interaction is centered on the second TNFR-like domain. Important residues were compared to critical positions in TNFR and CD40, another member of the TNFR family.