一个Ca(2+) 开关调整了calpain的活性位点
Tudor Moldoveanu1, Christopher M Hosfield, Daniel Lim
1Department of Biochemistry and the Protein, Engineering Network of Centres of Excellence, Queen's University, Kingston, Ontario, Canada.
Cell
|March 15, 2002
概括
(Ca2+) 结合激活calpains,蛋白酶参与细胞过程和疾病. 这项研究揭示了calpain中保存的双激活机制.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- (Ca2+) 信号调节calpains,蛋白酶对于细胞功能至关重要,如细胞骨重塑.
- 失调的水平和calpain活性与组织损伤 (缺血症) 和神经退行 (阿尔茨海默病) 有关.
研究的目的:
- 阐明结合机制对于激活mu-calpain的蛋白酶核心至关重要.
- 为了研究不同异构体中卡尔激活的进化保存.
主要方法:
- 在2.1A分辨率的X射线晶体学以确定mu-calpain蛋白酶核心的结构.
- 在各种calpain异型中对保存的结合残留物的分析.
主要成果:
- 晶体结构显示,激活mu-calpain蛋白酶核需要在两个新型非EF手部位的两个Ca2+) 离子的合作结合.
- 这些Ca2+) 结合残留的保存表明大多数calpains的一般,祖先激活机制,包括那些没有EF手域的calpains.
- 抑制剂calpastatin不会影响蛋白酶区域,这表明它在自保护酶释放时可能在病理中发挥作用.
结论:
- 一个保存的,双离子结合机制激活calpain蛋白酶核心,提供calpain激活的统一视图.
- 这种机制对calpains至关重要,它延伸到缺乏正规EF手域的异形.
- 对calpain激活及其与calpastatin独立的结构洞察力可能会为治疗calpain相关疾病的策略提供信息.
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