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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-04

AUTHORS

Stefan J. Riedl, Wenyu Li, Yang Chao, Robert Schwarzenbacher, Yigong Shi

ABSTRACT

Apoptosis is executed by caspases, which undergo proteolytic activation in response to cell death stimuli. The apoptotic protease-activating factor 1 (Apaf-1) controls caspase activation downstream of mitochondria. 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-A 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 alpha/beta 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. More... »

PAGES

926

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature03465

DOI

http://dx.doi.org/10.1038/nature03465

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1036690680

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15829969


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