Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model

Abstract

The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1,560-aa protein, which plays an important role in lysine methylation (specifically reverses tri- and di-methylation of Lys4 of histone H3). Currently, thirteen 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.

Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures

“…Noteworthily, the missense mutation KDM5C p.A388P, showed a protein intensity band of KDM5C and H3K4me3 similar to that of the WT. In line with the predicted impact on the protein conformation reported previously [ 47 ], we conclude that this missense mutation does not impair the demethylase activity but instead alters the binding to other proteins, perhaps involved into the recruitment of KDM5C to specific target promoters.…”

Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes‐Jensen syndrome

“…The D87G variant is at the N-terminal extreme of the A/T-rich interaction domain (ARID) that can bind both A/T-and C/Grich DNA sequences in vitro [72,73]. While this change could alter the ability of KDM5C to be recruited to some target genes, structural modeling studies suggest that this variant is unlikely to affect ARID-mediated DNA binding [74]. Instead, this change could affect protein-protein interactions necessary for KDM5C to regulate the expression of its target genes.…”

Investigatingd-lysine stereochemistry for epigenetic methylation, demethylation and recognition

“…Temporal atomistic molecular dynamic (MD) simulations were then used to investigate the relative flexibility of the readers and their ability to accommodate d -Kme3. MD approaches have proven to be valuable for elucidating properties concerning binding of histone PTM residues by epigenetic proteins 14,15. Previously, MD simulations (10 ns with the Amberff99sb force field) of H2AK5ac, H4K12ac, and H3K14ac binding to the BRPF1 bromodomain were used to understand selectivity 14.…”

“…Previously, MD simulations (10 ns with the Amberff99sb force field) of H2AK5ac, H4K12ac, and H3K14ac binding to the BRPF1 bromodomain were used to understand selectivity 14. Binding modes to the multi-domain JARID demethylase protein, KDM5C, have also been studied by MD (10 ns with Amberff14sb) 15…”