Caspase-9 is a critical factor in the initiation of apoptosis and as a result is tightly regulated by many mechanisms. Caspase-9 contains a Caspase Activation and Recruitment Domain (CARD), which enables caspase-9 to form a tight interaction with the apoptosome, a heptameric activating platform. The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site. The active sites of caspases are composed of four extremely mobile loops. When the active-site loops are not properly ordered, the CARD and core domains of caspase-9 do not interact and behave independently, like loosely tethered beads. When the active-site loop bundle is properly ordered, the CARD domain interacts with the catalytic core, forming a single folding unit. Taken together, these findings provide mechanistic insights into a new level of caspase-9 regulation, prompting speculation that the CARD may also play a role in the recruitment or recognition of substrate.
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March 2018
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Endoplasmic reticulum (ER) surrounding a cell nucleus. In this issue of the Biochemical Journal, Stupka et al. discuss the role of ER selenoproteins in the regulation of cellular stress responses. For further information, see pages 1037–1057.
Research Article|
March 29 2018
Caspase-9 CARD : core domain interactions require a properly formed active site
Jeanne A. Hardy
1Department of Chemistry, 104 LGRT, 710 N. Pleasant St, University of Massachusetts, Amherst, MA 01003, U.S.A.
Correspondence: Jeanne A. Hardy (hardy@chem.umass.edu)
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Publisher: Portland Press Ltd
Received:
December 01 2017
Revision Received:
February 27 2018
Accepted:
March 01 2018
Accepted Manuscript online:
March 02 2018
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (6): 1177–1196.
Article history
Received:
December 01 2017
Revision Received:
February 27 2018
Accepted:
March 01 2018
Accepted Manuscript online:
March 02 2018
Citation
Kristen L. Huber, Banyuhay P. Serrano, Jeanne A. Hardy; Caspase-9 CARD : core domain interactions require a properly formed active site. Biochem J 30 March 2018; 475 (6): 1177–1196. doi: https://doi.org/10.1042/BCJ20170913
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