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首页> 外文期刊>Biochemistry >Cysteine 81 Is Critical for the Interaction of S100A4 and Myosin-IIA
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Cysteine 81 Is Critical for the Interaction of S100A4 and Myosin-IIA

机译：半胱氨酸81是S100A4和肌球蛋白IIA相互作用的关键

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摘要

Overexpression of S100A4, a member of the S100 family of Ca~(2+)-binding proteins, is associated with a number of human pathologies, including fibrosis, inflammatory disorders, and metastatic disease. The identification of small molecules that disrupt S100A4/ target interactions provides a mechanism for inhibiting S100A4- mediated cellular activities and their associated pathologies. Using an anisotropy assay that monitors the Ca~(2+)-dependent binding of myosin- IIA to S100A4, NSC 95397 was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction and inhibits S100A4-mediated depolymerization of myosin-IIA filaments. Mass spectrometry demonstrated that NSC 95397 forms covalent adducts with Cys81 and Cys86, which are located in the canonical target binding cleft. Mutagenesis studies showed that covalent modification of just Cys81 is sufficient to inhibit S100A4 function with respect to myosin-IIA binding and depolymerization. Remarkably, substitution of Cys81 with serine or alanine significantly impaired the ability of S100A4 to promote myosin-IIA filament disassembly. As reversible covalent cysteine modifications have been observed for several S100 proteins, we propose that modification of Cys81 may provide an additional regulatory mechanism for mediating the binding of S100A4 to myosin-IIA.
机译：S100A4是Ca100（2+）结合蛋白S100家族的成员，其过表达与许多人类疾病有关，包括纤维化，炎性疾病和转移性疾病。破坏S100A4 /靶标相互作用的小分子的鉴定提供了一种抑制S100A4介导的细胞活性及其相关病理的机制。使用各向异性测定法监测肌球蛋白IIA与S100A4的Ca〜（2+）依赖性结合，将NSC 95397鉴定为一种抑制剂，可破坏S100A4 /肌球蛋白IIA的相互作用并抑制S100A4介导的肌球蛋白IIA细丝解聚。 。质谱分析表明，NSC 95397与Cys81和Cys86形成共价加合物，位于标准靶标结合裂隙中。诱变研究表明，就肌球蛋白IIA的结合和解聚而言，仅Cys81的共价修饰足以抑制S100A4的功能。值得注意的是，用丝氨酸或丙氨酸取代Cys81会大大削弱S100A4促进肌球蛋白IIA细丝分解的能力。由于已观察到几种S100蛋白的可逆共价半胱氨酸修饰，因此我们提出Cys81修饰可提供介导S100A4与肌球蛋白IIA结合的其他调控机制。

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