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首页> 外文期刊>Biochemistry >Intrinsically Disordered PEP-19 Confers Unique Dynamic Properties to Apo and Calcium Calmodulin
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Intrinsically Disordered PEP-19 Confers Unique Dynamic Properties to Apo and Calcium Calmodulin

机译：本质上无序的PEP-19为Apo和钙调钙蛋白赋予独特的动力学性质

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摘要

PEP-19 (Purkinje cell protein 4) is an intrinsically disordered protein with an IQcalmodulin (CaM)nbinding motif. Expression of PEP-19 was recently shown to protect cells from apoptosis and cell death due tonCa2þ overload. Our initial studies showed that PEP-19 causes novel and dramatic increases in the rates ofnassociation of Ca2þ with and dissociation of Ca2þ from the C-domain of CaM. The goal of this work was tonstudy interactions between the C-domain of CaM (C-CaM) and PEP-19 by solution nuclear magneticnresonance (NMR) to identify mechanisms by which PEP-19 regulates binding of Ca2þ to CaM. Our resultsnshow that PEP-19 causes a greater structural change in apo C-CaM than in Ca2þ-C-CaM, and that the firstnCa2þ binds preferentially to site IV in the presence of PEP-19 with exchange characteristics that are consistentnwith a decrease in Ca2þ binding cooperativity. Relatively weak binding of PEP-19 has distinct effects onnchemical and conformational exchange on the microsecond to millisecond time scale. In apo C-CaM, PEP-19nbinding causes a redistribution of residues that experience conformational exchange, leading to an increasenin the number of residues around Ca2þ binding site IV that undergo conformational exchange on thenmicrosecond to millisecond time scale. This appears to be caused by an allosteric effect because these residuesnare not localized to the PEP-19 binding site. In contrast, PEP-19 increases the number of residues that exhibitnconformational exchange in Ca2þ-C-CaM. These residues are primarily localized to the PEP-19 binding sitenbut also include Asp93 in site III. These results provide workingmodels for the role of protein dynamics in thenregulation of binding of Ca2þ to CaM by PEP-19.
机译：PEP-19（浦肯野细胞蛋白4）是一种具有IQcalmodulin（CaM）n结合基序的内在无序蛋白。最近显示，PEP-19的表达可保护细胞免受tonCa2 +超载引起的细胞凋亡和细胞死亡。我们的初步研究表明，PEP-19导致Ca2 +与CaM的C结构域的解离速率和Ca2 +从CaM的C结构域解离的速率发生了新颖而显着的增加。这项工作的目的是通过溶液核磁共振（NMR）研究CaM的C结构域（C-CaM）和PEP-19之间的相互作用，以鉴定PEP-19调节Ca2 +与CaM结合的机制。我们的结果表明，PEP-19在apo C-CaM中引起的结构变化大于Ca2 + -C-CaM，并且在PEP-19存在的情况下firstnCa2þ优先结合位点IV，其交换特征与Ca2þ的减少一致绑定合作性。 PEP-19的相对较弱的结合在微秒至毫秒的时间尺度上对化学和构象交换具有明显的影响。在载脂蛋白C-CaM中，PEP-19n结合引起经历构象交换的残基的重新分布，从而导致在Ca 2+结合位点IV周围经过微秒至毫秒级的构象交换的残基数目增加。这似乎是由于变构作用引起的，因为这些残基不位于PEP-19结合位点。相反，PEP-19增加了Ca2 + -C-CaM中构象交换的残基数量。这些残基主要位于PEP-19结合位点，但在位点III中也包括Asp93。这些结果为蛋白质动力学在随后通过PEP-19调节Ca 2+与CaM的结合中的作用提供了工作模型。

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