The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities

Chu-Chiao Wu, Sunhee Lee, Srinivas Malladi, Miao- Der Chen, Nicholas J. Mastrandrea, Zhiwen Zhang and Shawn B. Bratton ()
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Chu-Chiao Wu: The University of Texas MD Anderson Cancer Center
Sunhee Lee: The University of Texas MD Anderson Cancer Center
Srinivas Malladi: Institute for Cellular and Molecular Biology, The University of Texas at Austin
Miao- Der Chen: The University of Texas MD Anderson Cancer Center
Nicholas J. Mastrandrea: The University of Texas MD Anderson Cancer Center
Zhiwen Zhang: Santa Clara University
Shawn B. Bratton: The University of Texas MD Anderson Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract According to dogma, initiator caspases are activated through proximity-induced homodimerization, but some studies infer that during apoptosis caspase-9 may instead form a holoenzyme with the Apaf-1 apoptosome. Using several biochemical approaches, including a novel site-specific crosslinking technique, we provide the first direct evidence that procaspase-9 homodimerizes within the apoptosome, markedly increasing its avidity for the complex and inducing selective intramolecular cleavage at Asp-315. Remarkably, however, procaspase-9 could also bind via its small subunit to the NOD domain in Apaf-1, resulting in the formation of a heterodimer that more efficiently activated procaspase-3. Following cleavage, the intersubunit linker (and associated conformational changes) in caspase-9-p35/p12 inhibited its ability to form homo- and heterodimers, but feedback cleavage by caspase-3 at Asp-330 removed the linker entirely and partially restored activity to caspase-9-p35/p10. Thus, the apoptosome mediates the formation of caspase-9 homo- and heterodimers, both of which are impacted by cleavage and contribute to its overall function.

Date: 2016
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DOI: 10.1038/ncomms13565

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