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

J. Majkut, M. Sgobba, C. Holohan, N. Crawford, A. E. Logan, E. Kerr, C. A. Higgins, K. L. Redmond, J. S. Riley, I. Stasik, D. A. Fennell, S. Van Schaeybroeck, S. Haider, P. G. Johnston, D. Haigh and D. B. Longley ()
Additional contact information
J. Majkut: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
M. Sgobba: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
C. Holohan: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
N. Crawford: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
A. E. Logan: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
E. Kerr: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
C. A. Higgins: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
K. L. Redmond: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
J. S. Riley: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
I. Stasik: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
D. A. Fennell: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
S. Van Schaeybroeck: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
S. Haider: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
P. G. Johnston: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
D. Haigh: Centre for Cancer Research and Cell Biology, Queen’s University Belfast
D. B. Longley: Centre for Cancer Research and Cell Biology, Queen’s University Belfast

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4350

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