施一公2014-04-14 4:00 PM

c-FLIPL对蛋白酶原8的活化机制  Mechanism of procaspase-8 activation by c-FLIPL

论文摘要

细胞FLICE抑制蛋白(C-FLIP(L))是外源性细胞死亡途径的关键调节因子。虽然人们普遍将其认为是引发半胱天冬活性和细胞死亡的抑制剂,c-FLIP(L)也能够通过它们各自蛋白酶结构域的异二聚体增强蛋白酶原- 8的激活。但是此激活过程的基本机制依然神秘。在此我们表明,c- FLIP(L)通过蛋白酶原-8的亚基间连接体的裂解通过提高这两种蛋白之间的异二聚体加强了其激活过程,极大地提高了未处理C型蛋白酶-8的蛋白水解活性。C-FLIP(L)蛋白酶样结构域以及它与酶原C8复杂物的晶体结构能通过蛋白酶原-同源二聚化来识别有利于异二聚体的独特决定簇,并且能将酶原C8的潜在活性位点诱导入有效的构象中。总之,这些研究结果提供了对c-FLIP(L)在不同细胞环境中调制蛋白酶原-8活化来引起不同反应的关键功能方面的分子见解。

Abstract
Cellular FLICE-inhibitory protein (c-FLIP(L)) is a key regulator of the extrinsic cell death pathway. Although widely regarded as an inhibitor of initiator caspase activation and cell death, c-FLIP(L) is also capable of enhancing procaspase-8 activation through heterodimerization of their respective protease domains. However, the underlying mechanism of this activation process remains enigmatic. Here, we demonstrate that cleavage of the intersubunit linker of c-FLIP(L) by procaspase-8 potentiates the activation process by enhancing heterodimerization between the two proteins and vastly improving the proteolytic activity of unprocessed caspase-(C)8. The crystal structures of the protease-like domain of c-FLIP(L) alone and in complex with zymogen C8 identify the unique determinants that favor heterodimerization over procaspase-8 homodimerization, and induce the latent active site of zymogen C8 into a productive conformation. Together, these findings provide molecular insights into a key aspect of c-FLIP(L) function that modulates procaspase-8 activation to elicit diverse responses in different cellular contexts.

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