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

Majkut, Joanna and Sgobba, Miriam and Holohan, Caitriona and Crawford, Nyree and Logan, Andrew and Kerr, Emma and Higgins, Catherine and Redmond, Keara and Riley, Joel and Stasik, Izabela and Fennell, Dean and Van Schaeybroeck, Sandra and Haider, Shozeb and Johnston, Patrick and Haigh, David and Longley, Daniel (2014) Differential affinity of FLIP and procaspase 8 for FADD's DED binding surfaces regulates DISC assembly. Nature Communications, 5. ISSN 2041-1723

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Official URL: http://www.nature.com/ncomms/2014/140228/ncomms435...

Abstract

"Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages DEDs in 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: Article
Additional Information and Comments: http://www.nature.com/ncomms/2014/140228/ncomms4350/full/ncomms4350.html
Keywords: FLIP; FADD; caspase 8; DISC; DR5; apoptosis
Faculty / Department: Faculty of Science > School of Health Sciences
Depositing User: Karen Foxton
Date Deposited: 25 Feb 2016 11:29
Last Modified: 25 Feb 2016 11:29
URI: http://hira.hope.ac.uk/id/eprint/780

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