Moldoveanu Tudor, Hosfield Christopher M, Lim Daniel, Elce John S, Jia Zongchao, Davies Peter L
Department of Biochemistry and the Protein, Engineering Network of Centres of Excellence, Queen's University, Kingston, Ontario, Canada.
Cell. 2002 Mar 8;108(5):649-60. doi: 10.1016/s0092-8674(02)00659-1.
Ca(2+) signaling by calpains leads to controlled proteolysis during processes ranging from cytoskeleton remodeling in mammals to sex determination in nematodes. Deregulated Ca(2+) levels result in aberrant proteolysis by calpains, which contributes to tissue damage in heart and brain ischemias as well as neurodegeneration in Alzheimer's disease. Here we show that activation of the protease core of mu calpain requires cooperative binding of two Ca(2+) atoms at two non-EF-hand sites revealed in the 2.1 A crystal structure. Conservation of the Ca(2+) binding residues defines an ancestral general mechanism of activation for most calpain isoforms, including some that lack EF-hand domains. The protease region is not affected by the endogenous inhibitor, calpastatin, and may contribute to calpain-mediated pathologies when the core is released by autoproteolysis.
钙蛋白酶介导的Ca(2+)信号传导在从哺乳动物的细胞骨架重塑到线虫的性别决定等一系列过程中导致可控的蛋白质水解。Ca(2+)水平失调会导致钙蛋白酶异常的蛋白质水解，这会导致心脏和脑缺血中的组织损伤以及阿尔茨海默病中的神经退行性变。在这里，我们表明，μ-钙蛋白酶蛋白酶核心的激活需要两个Ca(2+)原子在2.1 Å晶体结构中揭示的两个非EF-手型位点上协同结合。Ca(2+)结合残基的保守性定义了大多数钙蛋白酶同工型激活的祖传一般机制，包括一些缺乏EF-手型结构域的同工型。蛋白酶区域不受内源性抑制剂钙蛋白酶抑制蛋白的影响，当核心通过自蛋白水解释放时，可能会导致钙蛋白酶介导的病理变化。
