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

AUTOR(ES)

Zhou, Pei

FONTE

The National Academy of Sciences

RESUMO

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 α-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.

Documentos Relacionados

• Caspase-9 and APAF-1 form an active holoenzyme
• Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation
• Oligomerization and activation of caspase-9, induced by Apaf-1 CARD
• A New Model for the Transition of APAF-1 from Inactive Monomer to Caspase-activating Apoptosome*
• Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1