Ca(II) and Zn(II) Cooperate To Modulate the Structure and Self-Assembly of S100A12.
Ca(II) and Zn(II) Cooperate To Modulate the Structure and Self-Assembly of S100A12.
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Ca(II) 和 Zn(II) 协同调节 S100A12 的结构和自组装。
DOI：
10.1021/acs.biochem.9b00123
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发表时间：
2019
期刊：
影响因子：
2.9
通讯作者：
Gupta,Rupal
中科院分区：
文献类型：
--
作者：
Wang,Qian;Aleshintsev,Aleksey;Bolton,David;Zhuang,Jianqin;Brenowitz,Michael;Gupta,Rupal
S100A12是钙离子结合蛋白S100家族中的一员，该家族在人类先天免疫系统中发挥作用。当蛋白质由中性粒细胞分泌时，S100A12对锌的固存具有抗菌活性。在这里，我们证明了钙离子与S100A12的S EF-Hand基序的结合以及锌离子与其二聚体界面的结合共同诱导了蛋白质的可逆自组装。溶液和魔角旋转核磁共振波谱对apo-，Ca~(2+)，Zn~(2+)和Ca~(2+)，Zn~(2+)-S100A12的研究表明，金属结合诱导的化学位移扰动指示着构象的变化，发生在整个多肽链上。这些扰动不是源于蛋白质二级结构的变化，蛋白质的二级结构在很大程度上仍然保持着。虽然S100A12的整体结构以钙离子结合为主，但锌离子与钙离子-S100A12的结合使螺旋II和铰链结构域(残基38-53)发生了额外的结构变化。S100A12的铰链结构域参与促进单核细胞趋化、急性炎症反应和产生水肿的分子相互作用。在Ca~(2+)-S100A12中，螺旋II和铰链区参与与晚期糖基化产物受体(RAGE)的C型免疫球蛋白结构域的结合。我们讨论了在锌离子结合时引入这些结构域的额外构象变化如何也影响S100A12与靶蛋白如RAGE的相互作用。
S100A12 is a member of the Ca2+binding S100 family of proteins that functions within the human innate immune system. Zinc sequestration by S100A12 confers antimicrobial activity when the protein is secreted by neutrophils. Here, we demonstrate that Ca2+binding to S100A12’s EF-hand motifs and Zn2+binding to its dimeric interface cooperate to induce reversible self-assembly of the protein. Solution and magic angle spinning nuclear magnetic resonance spectroscopy on apo-, Ca2+-, Zn2+-, and Ca2+,Zn2+-S100A12 shows that significant metal binding-induced chemical shift perturbations, indicative of conformational changes, occur throughout the polypeptide chain. These perturbations do not originate from changes in the secondary structure of the protein, which remains largely preserved. While the overall structure of S100A12 is dominated by Ca2+binding, Zn2+binding to Ca2+-S100A12 introduces additional structural changes to helix II and the hinge domain (residues 38–53). The hinge domain of S100A12 is involved in the molecular interactions that promote chemotaxis for human monocyte, acute inflammatory responses and generates edema. In Ca2+-S100A12, helix II and the hinge domain participate in binding with the C-type immunoglobulin domain of the receptor for advanced glycation products (RAGE). We discuss how the additional conformational changes introduced to these domains upon Zn2+binding may also impact the interaction of S100A12 and target proteins such as RAGE.