title: In silico Structural characterization of podocin and assessment of nephrotic syndrome-associated podocin mutants.
abstract: 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 contributes 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. © 2016 IUBMB Life, 68(7):578-588, 2016.
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Sandeep Kumar Narasimha
authors.initials: SK
authors.lastname: Mulukala
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Rajkishor
authors.initials: R
authors.lastname: Nishad
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Lakshmi Prasanna
authors.initials: LP
authors.lastname: Kolligundla
authors.affiliation: Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Biotechnology and Bioinformatics, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Nagu Prakash
authors.initials: NP
authors.lastname: Prabhu
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Pasupulati
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics; D003198:Computer Simulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000473:pathology; D050199:Podocytes / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C407223:NPHS2 protein
keywords: molecular modeling; nephrotic syndrome; podocin; podocytes; proteinuria; slit diaphragm