Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain
Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain
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DOI：
10.1074/jbc.m507475200
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发表时间：
2005-11-11
影响因子：
4.8
通讯作者：
Gong, CX
中科院分区：
文献类型：
--
作者：
Liu, F;Grundke-Iqbal, I;Gong, CX
钙稳态的紊乱被认为在阿尔茨海默病（AD）患者大脑的神经变性中发挥着重要作用，但其导致该疾病的分子途径尚不清楚。在这里，我们研究了 AD 大脑中两种主要 Ca2+ 调节的脑蛋白（钙蛋白酶和钙调磷酸酶）的激活。我们发现钙蛋白酶 I 被激活，进而裂解并激活 AD 大脑中的钙调神经磷酸酶。质谱分析表明，钙调神经磷酸酶被钙蛋白酶 I 切割在赖氨酸 501 处，即自抑制结构域 C 端的位置，产生 57 kDa 的截短形式。 57-kDa 钙调磷酸酶保持其磷酸酶活性的 Ca2+/钙调蛋白依赖性，但磷酸酶活性在截短后显着激活。钙调神经磷酸酶的裂解和激活与人脑中神经原纤维缠结的数量相关。这些发现表明钙蛋白酶 I 和钙调神经磷酸酶的过度激活可能介导钙稳态紊乱在 AD 神经变性中的作用。
A disturbance of calcium homeostasis is believed to play an important role in the neurodegeneration of the brains of Alzheimer disease ( AD) patients, but the molecular pathways by which it contributes to the disease are not well understood. Here we studied the activation of two major Ca2+-regulated brain proteins, calpain and calcineurin, in AD brain. We found that calpain I is activated, which in turn cleaves and activates calcineurin in AD brain. Mass spectrometric analysis indicated that the cleavage of calcineurin by calpain I is at lysine 501, a position C-terminal to the autoinhibitory domain, which produces a 57-kDa truncated form. The 57-kDa calcineurin maintains its Ca2+/calmodulin dependence of the phosphatase activity, but the phosphatase activity is remarkably activated upon truncation. The cleavage and activation of calcineurin correlate to the number of neurofibrillary tangles in human brains. These findings suggest that the overactivation of calpain I and calcineurin may mediate the role of calcium homeostatic disturbance in the neurodegeneration of AD.