Structural and biochemical basis of apoptotic activation by Smac/DIABLO.

Abstract:

:Apoptosis (programmed cell death), an essential process in the development and homeostasis of metazoans, is carried out by caspases. The mitochondrial protein Smac/DIABLO performs a critical function in apoptosis by eliminating the inhibitory effect of IAPs (inhibitor of apoptosis proteins) on caspases. Here we show that Smac/DIABLO promotes not only the proteolytic activation of procaspase-3 but also the enzymatic activity of mature caspase-3, both of which depend upon its ability to interact physically with IAPs. The crystal structure of Smac/DIABLO at 2.2 A resolution reveals that it homodimerizes through an extensive hydrophobic interface. Missense mutations inactivating this dimeric interface significantly compromise the function of Smac/DIABLO. As in the Drosophila proteins Reaper, Grim and Hid, the amino-terminal amino acids of Smac/DIABLO are indispensable for its function, and a seven-residue peptide derived from the amino terminus promotes procaspase-3 activation in vitro. These results establish an evolutionarily conserved structural and biochemical basis for the activation of apoptosis by Smac/DIABLO.

journal_name

Nature

journal_title

Nature

authors

Chai J,Du C,Wu JW,Kyin S,Wang X,Shi Y

doi

10.1038/35022514

keywords:

subject

Has Abstract

pub_date

2000-08-24 00:00:00

pages

855-62

issue

6798

eissn

0028-0836

issn

1476-4687

journal_volume

406

pub_type

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