Bang, S Jeong, EJ Kim, IK Jung, YK Kim, KS 2024-01-21T13:13:46Z 2024-01-21T13:13:46Z 2021-09-05 2000-11 0021-9258 https://pubs.kist.re.kr/handle/201004/140990 FADD is known to function as a common signaling conduit in Fas- and tumor necrosis factor (TNF)-mediated apoptosis, The convergent death signals from the Fas receptor and TNF receptor 1 are transferred to FADD by death domain interactions triggering the same cellular event, caspase-8 activation. In this work, we investigated whether the same binding surface of FADD is used for both signaling pathways by using FADD death domain mutants. Mutations in helices alpha2 and alpha3 of the FADD death domain, the interacting surface with the Fas death domain, affected TNF-mediated apoptosis to various extents. This indicated that TNF-mediated apoptosis uses the same binding surface of the FADD death domain as Fas-mediated apoptosis. The binding specificity is not the same, however. Some mutations affected the binding affinity of the Fas death domain for the FADD death domain, but did not influence TNF-mediated apoptosis and vice versa, Interestingly, all mutants tested that affected TNF-mediated apoptosis have structural perturbations, implying that the structural integrity, involving helices alpha2 and alpha3 in particular, is critical in TNF-mediated apoptosis. Our results suggest that different signaling molecules use a similar structural interaction to trigger the same cellular event, such as caspase-8 recruitment, which could be typical in convergent signal transduction. English AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC Fas- and tumor necrosis factor-mediated apoptosis uses the same binding surface of FADD to trigger signal transduction - A typical model for convergent signal transduction Article 10.1074/jbc.M006620200 1 JOURNAL OF BIOLOGICAL CHEMISTRY, v.275, no.46, pp.36217 - 36222 JOURNAL OF BIOLOGICAL CHEMISTRY 275 46 36217 36222 N scie scopus 000165382000081 2-s2.0-0034680899 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article 1-ASSOCIATED PROTEIN TRADD DEATH DOMAIN CELL-DEATH TNF RECEPTOR MUTATIONAL ANALYSIS CD95 FAS/APO-1 COMPLEX PATHWAYS ANTIGEN