Structure of the apoptotic protease-activating factor 1 bound to ADP

Stefan J. Riedl, Wenyu Li, Yang Chao, Robert Schwarzenbacher and Yigong Shi ()
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Stefan J. Riedl: Princeton University, Lewis Thomas Laboratory
Wenyu Li: Princeton University, Lewis Thomas Laboratory
Yang Chao: Princeton University, Lewis Thomas Laboratory
Robert Schwarzenbacher: University of California-San Diego
Yigong Shi: Princeton University, Lewis Thomas Laboratory

Nature, 2005, vol. 434, issue 7035, 926-933

Abstract: Abstract Apoptosis is executed by caspases, which undergo proteolytic activation in response to cell death stimuli1. The apoptotic protease-activating factor 1 (Apaf-1) controls caspase activation downstream of mitochondria2. During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 (ref. 2). The mechanisms underlying Apaf-1 function are largely unknown. Here we report the 2.2-Å crystal structure of an ADP-bound, WD40-deleted Apaf-1, which reveals the molecular mechanism by which Apaf-1 exists in an inactive state before ATP binding. The amino-terminal caspase recruitment domain packs against a three-layered α/β fold, a short helical motif and a winged-helix domain, resulting in the burial of the caspase-9-binding interface. The deeply buried ADP molecule serves as an organizing centre to strengthen interactions between these four adjoining domains, thus locking Apaf-1 in an inactive conformation. Apaf-1 binds to and hydrolyses ATP/dATP and their analogues. The binding and hydrolysis of nucleotides seem to drive conformational changes that are essential for the formation of the apoptosome and the activation of caspase-9.

Date: 2005
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DOI: 10.1038/nature03465

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