3H11

Zymogen caspase-8:c-FLIPL protease domain complex

3H11 の概要

• エントリーDOI: 10.2210/pdb3h11/pdb
• 関連するPDBエントリー: 3H13
• 分子名称: CASP8 and FADD-like apoptosis regulator, Caspase-8, IETD aldehyde inhibitor, ... (4 entities in total)
• 機能のキーワード: cell death, apoptosis, caspase, alternative splicing, host-virus interaction, polymorphism, cytoplasm, disease mutation, hydrolase, phosphoprotein, protease, thiol protease, zymogen
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: Q14790
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 62982.91

構造登録者

Jeffrey, P.D.,Yu, J.W.,Shi, Y. (登録日: 2009-04-10, 公開日: 2009-04-28, 最終更新日: 2024-11-27)

主引用文献

Yu, J.W.,Jeffrey, P.D.,Shi, Y.
Mechanism of procaspase-8 activation by c-FLIPL.
Proc.Natl.Acad.Sci.USA, 106:8169-8174, 2009

PubMed 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.

PubMed: 19416807
DOI: 10.1073/pnas.0812453106

実験手法

X-RAY DIFFRACTION (1.9 Å)