1. Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA
2. Joint Center for Structural Genomics, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

Correspondence to: Yigong Shi¹ Correspondence and requests for materials should be addressed to Y.S. (Email: yshi@molbio.princeton.edu).
The atomic coordinates have been deposited with the Protein Data Bank with the accession number 1Z6T.

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 / 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.

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