期刊
SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-018-35153-5
关键词
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资金
- NSFC [21521003, 81373326, 21290183, 81400826]
- program of the Science and Technology committee of Guangdong [2014A030312004, 2015A030313887]
- Shenzhen Science and Technology innovation program [JCYJ20150529095420031, JCYJ20170412150827191, JCYJ20170818090609800]
Caspase-8 is an apoptotic protease that is activated by a proximity-induced dimerization mechanism within the death-inducing signaling complex (DISC). The death effector domain (DED) of caspase-8 is involved in protein-protein interactions and is essential for the activation. Here, we report two crystal structures of the dimeric DEDs of the F122A mutant of caspase-8, both of which illustrate a novel domain-swapped dimerization, while differ in the relative orientation of the two subunits and the solvent exposure of the conserved hydrophobic patch Phe122/Leu123. We demonstrate that mutations disrupting the dimerization of the DEDs abrogate the formation of cellular death effector filaments (DEFs) and the induced apoptosis by overexpressed DEDs. Furthermore, such dimerization-disrupting mutations also impair the activation of the full-length caspase-8 and the downstream apoptosis cascade. The structures provide new insights into understanding the mechanism underlying the activation of procaspase-8 within the DISC and DEFs.
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