C2 domains are the second-most abundant calcium binding module in the proteome. Activity of the muscular dystrophy associated protein dysferlin is dependent on the C2A domain at the N-terminus of the protein, which couples calcium and PI(4,5)P2 binding through an unknown mechanism. Using solution state nuclear magnetic resonance spectroscopy we confirm the phosphoinositide binding site for the domain and find that calcium binding attenuates millisecond to microsecond motions at both in the calcium binding loops and the concave face of the C2A, including a portion of the phosphoinositide binding site. Our results support a model whereby increasing calcium concentrations shift the phosphoinositide binding pocket of C2A into a binding-competent state, allowing for calcium dependent membrane targeting. This model contrasts with the canonical mechanism for C2 domain-phosphoinositide interaction and provides a basis for how pathogenic mutations in the C2A domain result in loss of function and disease.

中文翻译：

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钙敏感性变构调节Dysferlin C2A域的PI（4,5）P2结合位点。

C2结构域是蛋白质组中第二丰富的钙结合模块。肌营养不良症相关蛋白dysferlin的活性取决于该蛋白N端的C2A域，该域通过未知机制偶联钙和PI（4,5）P2结合。使用溶液状态核磁共振波谱我们确定了该域的磷酸肌醇结合位点，发现钙结合在钙结合环和C2A的凹面（包括一部分磷酸肌醇结合位点）上都减弱了毫秒到微秒的运动。我们的结果支持一个模型，通过该模型，钙浓度的增加将C2A的磷酸肌醇结合口袋转变为可结合状态，从而实现钙依赖性膜靶向。