3BOW

Structure of M-calpain in complex with Calpastatin

3BOW の概要

• エントリーDOI: 10.2210/pdb3bow/pdb
• 関連するPDBエントリー: 1df0 1kfu 1kxr
• 分子名称: Calpain-2 catalytic subunit, Calpain small subunit 1, Calpastatin, ... (5 entities in total)
• 機能のキーワード: cysteine protease, inhibitor, cell membrane, hydrolase, membrane, protease, thiol protease, phosphoprotein, protease inhibitor, thiol protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Rattus norvegicus (brown rat,rat,rats); 詳細
• 細胞内の位置: Cytoplasm (By similarity): Q07009; Cytoplasm: Q64537
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 114049.26

構造登録者

Hanna, R.A.,Campbell, R.L.,Davies, P.L. (登録日: 2007-12-17, 公開日: 2008-11-25, 最終更新日: 2023-08-30)

主引用文献

Hanna, R.A.,Campbell, R.L.,Davies, P.L.
Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin.
Nature, 456:409-412, 2008

PubMed Abstract: Calpains are non-lysosomal calcium-dependent cysteine proteinases that selectively cleave proteins in response to calcium signals and thereby control cellular functions such as cytoskeletal remodelling, cell cycle progression, gene expression and apoptotic cell death. In mammals, the two best-characterized members of the calpain family, calpain 1 and calpain 2 (micro-calpain and m-calpain, respectively), are ubiquitously expressed. The activity of calpains is tightly controlled by the endogenous inhibitor calpastatin, which is an intrinsically unstructured protein capable of reversibly binding and inhibiting four molecules of calpain, but only in the presence of calcium. To date, the mechanism of inhibition by calpastatin and the basis for its absolute specificity have remained speculative. It was not clear how this unstructured protein inhibits calpains without being cleaved itself, nor was it known how calcium induced changes that facilitated the binding of calpastatin to calpain. Here we report the 2.4-A-resolution crystal structure of the calcium-bound calpain 2 heterodimer bound by one of the four inhibitory domains of calpastatin. Calpastatin is seen to inhibit calpain by occupying both sides of the active site cleft. Although the inhibitor passes through the active site cleft it escapes cleavage in a novel manner by looping out and around the active site cysteine. The inhibitory domain of calpastatin recognizes multiple lower affinity sites present only in the calcium-bound form of the enzyme, resulting in an interaction that is tight, specific and calcium dependent. This crystal structure, and that of a related complex, also reveal the conformational changes that calpain undergoes on binding calcium, which include opening of the active site cleft and movement of the domains relative to each other to produce a more compact enzyme.

PubMed: 19020623
DOI: 10.1038/nature07451

実験手法

X-RAY DIFFRACTION (2.4 Å)