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DED 结构域相互作用 FADD 和 Caspase-8 在诱导细胞凋亡中的作用。

DED Interaction of FADD and Caspase-8 in the Induction of Apoptotic Cell Death.

机构信息

Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea.

出版信息

J Microbiol Biotechnol. 2022 Aug 28;32(8):1034-1040. doi: 10.4014/jmb.2206.06003. Epub 2022 Jul 25.

DOI:10.4014/jmb.2206.06003
PMID:35879276
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9628938/
Abstract

Fas-associated death domain (FADD) is an adapter molecule that bridges the interaction between receptor-interacting protein 1 (RIP1) and aspartate-specific cysteine protease-8 (caspase-8). As the primary mediator of apoptotic cell death, caspase-8 has two N-terminal death-effector domains (DEDs) and it interacts with other proteins in the DED subfamily through several conserved residues. In the tumor necrosis receptor-1 (TNFR-1)-dependent signaling pathway, apoptosis is triggered by the caspase-8/FADD complex by stimulating receptor internalization. However, the molecular mechanism of complex formation by the DED proteins remains poorly understood. Here, we found that direct DED-DED interaction between FADD and caspase-8 and the structure-based mutations (Y8D/I128A, E12A/I128A, E12R/I128A, K39A/I128A, K39D/I128A, F122A/I128A, and L123A/I128A) of caspase-8 disrupted formation of the stable DED complex with FADD. Moreover, the monomeric crystal structure of the caspase-8 DEDs (F122A/I128A) was solved at 1.7 Å. This study will provide new insight into the interaction mechanism and structural characteristics between FADD and caspase-8 DED subfamily proteins.

摘要

Fas 相关死亡结构域（FADD）是一种衔接分子，它连接着受体相互作用蛋白 1（RIP1）和天冬氨酸特异性半胱氨酸蛋白酶-8（caspase-8）之间的相互作用。作为细胞凋亡的主要介导者，caspase-8 有两个 N 端死亡效应结构域（DED），并通过几个保守残基与 DED 亚家族中的其他蛋白质相互作用。在肿瘤坏死受体-1（TNFR-1）依赖性信号通路中，caspase-8/FADD 复合物通过刺激受体内化来触发细胞凋亡。然而，DED 蛋白复合物形成的分子机制仍知之甚少。在这里，我们发现 FADD 和 caspase-8 的直接 DED-DED 相互作用以及基于结构的突变（Y8D/I128A、E12A/I128A、E12R/I128A、K39A/I128A、K39D/I128A、F122A/I128A 和 L123A/I128A）破坏了 caspase-8 与 FADD 形成稳定 DED 复合物的能力。此外，还解析了 caspase-8 DED （F122A/I128A）单体晶体结构，分辨率为 1.7Å。这项研究将为 FADD 和 caspase-8 DED 亚家族蛋白之间的相互作用机制和结构特征提供新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/d4d2ec0f84db/jmb-32-8-1034-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/678f3b51e9f0/jmb-32-8-1034-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/3205855199a4/jmb-32-8-1034-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/f7079d401a13/jmb-32-8-1034-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/d4d2ec0f84db/jmb-32-8-1034-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/678f3b51e9f0/jmb-32-8-1034-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/3205855199a4/jmb-32-8-1034-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/f7079d401a13/jmb-32-8-1034-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/53d7/9628938/d4d2ec0f84db/jmb-32-8-1034-f4.jpg

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