A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2001-03

AUTHORS

Srinivasa M. Srinivasula, Ramesh Hegde, Ayman Saleh, Pinaki Datta, Eric Shiozaki, Jijie Chai, Ryung-Ah Lee, Paul D. Robbins, Teresa Fernandes-Alnemri, Yigong Shi, Emad S. Alnemri

ABSTRACT

X-linked inhibitor-of-apoptosis protein (XIAP) interacts with caspase-9 and inhibits its activity, whereas Smac (also known as DIABLO) relieves this inhibition through interaction with XIAP. Here we show that XIAP associates with the active caspase-9-Apaf-1 holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspase-9, which becomes exposed after proteolytic processing of procaspase-9 at Asp315. Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition. We note that the N-terminal four residues of caspase-9 linker peptide share significant homology with the N-terminal tetra-peptide in mature Smac and in the Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding motifs. Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3. Our studies reveal a mechanism in which binding to the BIR3 domain by two conserved peptides, one from Smac and the other one from caspase-9, has opposing effects on caspase activity and apoptosis. More... »

PAGES

112

Journal

TITLE

Nature

ISSUE

6824

VOLUME

410

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/35065125

DOI

http://dx.doi.org/10.1038/35065125

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1019156927

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/11242052


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