In Silico Structural Characterization of Podocin and Assessment of Nephrotic Syndrome-Associated Podocin Mutants
In Silico Structural Characterization of Podocin and Assessment of Nephrotic Syndrome-Associated Podocin Mutants
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DOI：
10.1002/iub.1515
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发表时间：
2016-07-01
期刊：
影响因子：
4.6
通讯作者：
Pasupulati, Anil Kumar
中科院分区：
文献类型：
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作者：
Kumar, Sandeep;Mulukala, Narasimha;Pasupulati, Anil Kumar
肾病综合征(NS)表现为高蛋白尿、低蛋白血症和水肿。在参与NS病理生理的基因中，编码podocin的NPHS2基因突变最多。Podocin是一种完整的膜蛋白，属于胃动素家族，仅在足细胞中表达，定位于裂隙-横隔膜。已知Podocin的突变与类固醇抗药性NS和快速进展为终末期肾脏疾病有关，从而表明其在维持SD完整性和足细胞功能方面的作用。Podocin的结构洞察力尚不清楚，Podocin对SD的结构贡献的确切机制尚未阐明。在这项研究中，我们推导了一个人足叶素的模型，讨论了跨膜定位和内在非结构区域的细节，并提供了关于足叶素如何与其他SD组分相互作用的理解。在野生型Podocin及其与特发性NS相关的一些突变体中，对蛋白内相互作用进行了评估。Podocin的突变改变了先天的蛋白内相互作用，影响了Podocin的天然结构，以及它与下足细胞蛋白形成关键复合体的能力。(C)2016年IUBMB生命
Nephrotic syndrome (NS) is manifested by hyperproteinuria, hypoalbuminemia, and edema. NPHS2 that encodes podocin was found to have most mutations among the genes that are involved in the pathophysiology of NS. Podocin, an integral membrane protein belonging to stomatin family, is expressed exclusively in podocytes and is localized to slit-diaphragm (SD). Mutations in podocin are known to be associated with steroid-resistant NS and rapid progression to end-stage renal disease, thus signifying its role in maintaining SD integrity and podocyte function. The structural insights of podocin are not known, and the precise mechanism by which podocin con-tributes to the architecture of SD is yet to be elucidated. In this study, we deduced a model for human podocin, discussed the details of transmembrane localization and intrinsically unstructured regions, and provide an understanding of how podocin interacts with other SD components. Intraprotein interactions were assessed in wild-type podocin and in some of its mutants that are associated with idiopathic NS. Mutations in podocin alter the innate intraprotein interactions affecting the native structure of podocin and its ability to form critical complex with subpodocyte proteins. (C) 2016 IUBMB Life