Apoptosis requires recruitment of caspases by receptor-associated adaptors through homophilic interactions between the CARDs (caspase recruitment domains) of adaptor proteins and prodomains of caspases. We have solved the CARD structure of the RAIDD adaptor protein that recruits ICH- 1/caspase-2. It consists of six tightly packed helices arranged in a topology homologous to the Fas death domain. The surface contains a basic and an acidic patch on opposite sides. This polarity is conserved in the ICH-1 CARD as indicated by homology modeling. Mutagenesis data suggest that these patches mediate CARD/CARD interaction between RAIDD and ICH-1. Subsequent modeling of the CARDs of Apaf-1 and caspase-9, as well as Ced-4 and Ced-3, showed that the basic/acidic surface polarity is highly conserved, suggesting a general mode for CARD/CARD interaction.
Bibliographical noteFunding Information:
We thank Dr. Federico del Rio for help with the use of the J-doubling method for measuring coupling constants and Greg Heffron for help with the use of spectrometers. This research was supported by a grant from the National Institutes of Health (GM 38608 and GM 47467). Acquisition and maintenance of spectrometers and computers used for this work were supported by the National Science Foundation (MCB 9527181), the Harvard Center for Structural Biology, and the Giovanni Armenise-Harvard Foundation for Advanced Scientific Research.