Synthetic peptides corresponding to ligand-binding region of death receptors, DR5, Fas, and TNFR, specifically inhibit cell death mediated by the death ligands, respectively.
Apoptosis as well as cell growth and cell differentiation play an important role in the maintenance of homeostasis in multicellular organisms. Disruption of apoptosis causes serious diseases, such as cancer, chronic inflammatory diseases, and autoimmune diseases; therefore, the control of apoptosis is one of the most promising therapeutic approaches to these apoptosis-disrupted diseases. Apoptosis is mediated by soluble factors, which belong to the TNF superfamily, such as TNF-alpha, FasL, and TRAIL. Here, we report that we deduced ligand-binding domains based on the structure of apoptosis ligand-receptor complex, and the synthetic peptide corresponding to residues 91-102 of DR5 indeed showed specific binding to TRAIL molecule and inhibited TRAIL-induced cell death both in L929 cells and in HeLa cells. The other death receptor-derived peptides, which are the corresponding regions of TNFR1 and Fas, also showed specific binding to TNF-alpha and FasL and inhibited the ligand-induced cell death, respectively. These results suggest that the position of the ligand-binding region is conserved among these death-receptor family members, whereas the primary amino acid sequence determines ligand specificity.
Kajiwara
Kazumi
K
Graduate School of Materials Science, NARA Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Saito
Atsuhiro
A
Ogata
Shin-ichi
S
Tanihara
Masao
M
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D015703:Antigens, CD; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor