Cofactors‐loaded quaternary structure of lysine‐specific demethylase 5C (KDM5C) protein: Computational model. Issue 12 (1st October 2016)

• Record Type: Journal Article
• Authors: Peng, Yunhui; Alexov, Emil
• Is Part Of: Proteins. Volume 84:Issue 12(2016)
• Page Start: 1797
• Page End: 1809
• Publication Date: 2016-10-01
• Subjects: KDM5C gene -- quaternary structure -- missense mutations -- X‐linked mental retardation -- homology modeling -- inter‐domain interactions; Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.25162
• Languages: English
• ISSNs: 0887-3585

Abstract

ABSTRACT: The KDM5C gene (also known as JARID1C and SMCX ) is located on the X chromosome and encodes a ubiquitously expressed 1560‐aa protein, which plays an important role in lysine methylation (specifically reverses tri‐ and di‐methylation of Lys4 of histone H3). Currently, 13 missense mutations in KDM5C have been linked to X‐linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure. In this work, we utilize homology modeling, docking, and experimental data to predict 3D structures of KDM5C domains and their mutual arrangement. The resulting quaternary structure includes KDM5C JmjN, ARID, PHD1, JmjC, ZF domains, substrate histone peptide, enzymatic cofactors, and DNA. The predicted quaternary structure was investigated with molecular dynamic simulation for its stability, and further analysis was carried out to identify features measured experimentally. The predicted structure of KDM5C was used to investigate the effects of disease‐causing mutations and it was shown that the mutations alter domain stability and inter‐domain interactions. The structural model reported in this work could prompt experimental investigations of KDM5C domain‐domain interaction and exploration of undiscovered functionalities. Proteins 2016; 84:1797–1809. © 2016 Wiley Periodicals, Inc.