Yang Jin Kuk
Department of Chemistry, School of Natural Sciences, Soongsil University, Seoul, 156-743, Korea,
Apoptosis. 2015 Feb;20(2):235-9. doi: 10.1007/s10495-014-1060-6.
Death-inducing signaling complex (DISC) is a platform for the activation of initiator caspase in extrinsic apoptosis. Assembly of DISC is accomplished by two different types of homotypic interaction: one is between death domains (DDs) of a death receptor and FADD, and the other is between death effecter domains (DEDs) of FADD, procaspase-8/-10 and cFLIP. Recent biochemical investigations on the stoichiometry of DISC have revealed that single-DED-containing FADD exists in DISC in a substantially lower abundance than the sum of tandem-DEDs-containing components that are procaspase-8 and cFLIP. In addition, the homology models of the tandem DEDs in procaspase-8 and cFLIP show that two different interaction faces, H1-H4 face and H2-H5 face, are exposed for possible inter-molecular DED-DED interactions. These recent findings led to a proposal of the DED chain model for the interactions between FADD, procaspase-8 and cFLIP in DISC. This emerging view provides new insights on the topology of DED-DED network in DISC and furthermore on how procaspase-8 and cFLIP cluster for dimerization and proteolytic activation.
死亡诱导信号复合物（DISC）是细胞外凋亡中起始半胱天冬酶激活的平台。DISC的组装通过两种不同类型的同型相互作用完成：一种是死亡受体的死亡结构域（DD）与FADD之间的相互作用，另一种是FADD、前半胱天冬酶-8/-10和cFLIP的死亡效应结构域（DED）之间的相互作用。最近关于DISC化学计量的生化研究表明，含有单个DED的FADD在DISC中的丰度明显低于含有串联DED的组分（前半胱天冬酶-8和cFLIP）的总和。此外，前半胱天冬酶-8和cFLIP中串联DED的同源模型表明，两个不同的相互作用面，即H1-H4面和H2-H5面，暴露出来以进行可能的分子间DED-DED相互作用。这些最新发现导致了关于DISC中FADD、前半胱天冬酶-8和cFLIP之间相互作用的DED链模型的提出。这种新出现的观点为DISC中DED-DED网络的拓扑结构以及前半胱天冬酶-8和cFLIP如何聚集以进行二聚化和蛋白水解激活提供了新的见解。
