Differential affinity of FLIP and procaspase 8 for FADD’s DED binding surfaces regulates DISC assembly

Majkut, J. et al. (2014) Differential affinity of FLIP and procaspase 8 for FADD’s DED binding surfaces regulates DISC assembly. Nature Communications, 5, p. 3350. (doi: 10.1038/ncomms4350) (PMID:24577104) (PMCID:PMC3942653)

Abstract

Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages the DEDs of procaspase 8 and its inhibitor FLIP to form death-inducing signalling complexes (DISCs). The DEDs of FADD, FLIP and procaspase 8 interact with one another using two binding surfaces defined by α1/α4 and α2/α5 helices, respectively. Here we report that FLIP has preferential affinity for the α1/α4 surface of FADD, whereas procaspase 8 has preferential affinity for FADD’s α2/α5 surface. These relative affinities contribute to FLIP being recruited to the DISC at comparable levels to procaspase 8 despite lower cellular expression. Additional studies, including assessment of DISC stoichiometry and functional assays, suggest that following death receptor recruitment, the FADD DED preferentially engages FLIP using its α1/α4 surface and procaspase 8 using its α2/α5 surface; these tripartite intermediates then interact via the α1/α4 surface of FLIP DED1 and the α2/α5 surface of procaspase 8 DED2.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Riley, Dr Joel
• Authors: Majkut, J., Sgobba, M., Holohan, C., Crawford, N., Logan, A.E., Kerr, E., Higgins, C.A., Redmond, K.L., Riley, J.S., Stasik, I., Fennell, D.A., Van Schaeybroeck, S., Haider, S., Johnston, P.G., Haigh, D., and Longley, D.B.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723