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PMID: 10500165 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: a structural basis for specific adaptor/caspase interaction.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 20 ·1999-09-28 ·Pages 11265-70

Zhou P, Chou J, Olea RS, Yuan J, Wagner G

Abstract

Direct recruitment and activation of caspase-9 by Apaf-1 through the homophilic CARD/CARD (Caspase Recruitment Domain) interaction is critical for the activation of caspases downstream of mitochondrial damage in apoptosis. Here we report the solution structure of the Apaf-1 CARD domain and its surface of interaction with caspase-9 CARD. Apaf-1 CARD consists of six tightly packed amphipathic alpha-helices and is topologically similar to the RAIDD CARD, with the exception of a kink observed in the middle of the N-terminal helix. By using chemical shift perturbation data, the homophilic interaction was mapped to the acidic surface of Apaf-1 CARD centered around helices 2 and 3. Interestingly, a significant portion of the chemically perturbed residues are hydrophobic, indicating that in addition to the electrostatic interactions predicted previously, hydrophobic interaction is also an important driving force underlying the CARD/CARD interaction. On the basis of the identified functional residues of Apaf-1 CARD and the surface charge complementarity, we propose a model of CARD/CARD interaction between Apaf-1 and caspase-9.

MeSH Terms
Amino Acid Sequence Apoptotic Protease-Activating Factor 1 Caspase 9 Caspases/chemistry Humans Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data Proteins/chemistry
Chemicals
APAF1 protein, human Apoptotic Protease-Activating Factor 1 Proteins CASP9 protein, human Caspase 9 Caspases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Zhou P
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Chou J
Olea R S
Yuan J
Wagner G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.20.11265
Published
1999-09-28
Pages
11265-70
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18022
Subset
IM
Grants
NIGMS NIH HHS · R01 GM038608 · United States
NIGMS NIH HHS · GM 38608 · United States
Databases
PDB
1C15, RCSB009364
External Links
PubMed source DOI: 10.1073/pnas.96.20.11265 PMC Full Text View journal details
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