STRUCTURE OF A CED-4-CED-3 HOLOENZYME

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 细胞凋亡在后生动物的发育和稳态中起着重要作用。细胞凋亡作为生长和分化的内在组成部分的根本意义仅在最近十年中才被认识到，细胞死亡途径首先在秀丽隐杆线虫（C. habditis elegans）中被发现。elegans），然后是智人。麻省理工学院的Bob Horvitz和他的同事负责分离和表征四个基因（egl-1，ced-9，ced-4和ced-3），这些基因共同控制C.优雅CED-3是细胞杀伤半胱天冬酶，其活化需要CED-4。然而，CED-4如何促进CED-3的激活仍然完全未知。我们最近已经表明，CED-4形成八聚体，其仅募集CED-3单体的两个分子用于活化。活化的CED-3作为全酶保持与CED-4溶酶体结合。我们已经结晶了CED-4-CED-3复合物，并计划确定其结构。这项研究将揭示CED-4促进CED-3活化的分子机制。

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.