Structural basis for multifunctional roles of mammalian aminopeptidase N
Structural basis for multifunctional roles of mammalian aminopeptidase N
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DOI：
10.1073/pnas.1210123109
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发表时间：
2012-10-30
影响因子：
11.1
通讯作者：
Li, Fang
中科院分区：
文献类型：
--
作者：
Chen, Lang;Lin, Yi-Lun;Li, Fang
哺乳动物氨肽酶 N (APN) 在许多生理过程中发挥多功能作用，包括肽代谢、细胞运动和粘附以及冠状病毒进入。在这里，我们确定了 1.85 埃分辨率的猪 APN 及其与肽底物和多种抑制剂的复合物的晶体结构。 APN 是一种细胞表面锚定的海马形锌氨肽酶，可形成头对头二聚体。 APN 的这些结构以催化活性状态捕获，阐明了其氨肽酶活性的详细催化机制。 APN 的活性位点和肽结合通道位于具有宽开口的空腔中，可以轻松访问肽。空腔可能会进一步打开以结合暴露的蛋白质 N 末端。活性位点锚定肽/蛋白质的N端中性残基，肽结合通道以序列无关的方式结合肽/蛋白质的其余部分。 APN 还为冠状病毒的结合提供了暴露的外表面，而不影响其生理功能。这些结构特征使 APN 能够在肽代谢中普遍发挥作用，与其他蛋白质相互作用以介导细胞运动和粘附，并充当冠状病毒受体。这项研究阐明了 APN 的多功能作用，并可以指导 APN 相关疾病的治疗工作。
Mammalian aminopeptidase N (APN) plays multifunctional roles in many physiological processes, including peptide metabolism, cell motility and adhesion, and coronavirus entry. Here we determined crystal structures of porcine APN at 1.85 angstrom resolution and its complexes with a peptide substrate and a variety of inhibitors. APN is a cell surface-anchored and seahorse-shaped zinc-aminopeptidase that forms head-to-head dimers. Captured in a catalytically active state, these structures of APN illustrate a detailed catalytic mechanism for its aminopeptidase activity. The active site and peptide-binding channel of APN reside in cavities with wide openings, allowing easy access to peptides. The cavities can potentially open up further to bind the exposed N terminus of proteins. The active site anchors the N-terminal neutral residue of peptides/proteins, and the peptide-binding channel binds the remainder of the peptides/proteins in a sequence-independent fashion. APN also provides an exposed outer surface for coronavirus binding, without its physiological functions being affected. These structural features enable APN to function ubiquitously in peptide metabolism, interact with other proteins to mediate cell motility and adhesion, and serve as a coronavirus receptor. This study elucidates multifunctional roles of APN and can guide therapeutic efforts to treat APN-related diseases.