STRUCTURE OF A CED-4-CED-3 HOLOENZYME

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Apoptosis plays a central role in the development and homeostasis of metazoans. The fundamental significance of apoptosis as an intrinsic component of growth and differentiation was only realized in the last decade, with the discovery of the cell death pathway first in Caenorhabditis elegans (C. elegans) and then in homo sapiens. Bob Horvitz and his colleagues at MIT were responsible for the isolation and characterization of four genes (egl-1, ced-9, ced-4, and ced-3) that collectively control the onset of programmed cell death in C. elegans. CED-3 is the cell-killing caspase and its activation requires CED-4. However, how CED-4 facilitates the activation of CED-3 remains completely unknown. We have recently shown that CED-4 forms an octameric apoptosome, which only recruits two molecules of the CED-3 monomer for activation. The activated CED-3 remains bound to the CED-4 apoptosome as a holoenzyme. We have crystallized the CED-4-CED-3 complex and plan to determine its structure. The proposed study will reveal the molecular mechanisms by which CED-4 facilitates the activation of CED-3.