Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease

Abstract

Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified missense mutations (R108W, N142S, and R179H). We predict the ARID domain’s folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain), indicating their importance for the KDM5C function. N-terminal residues’ high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless.

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

“…ARID domain is the DNA binding domain of KDM5C protein and a NMR structure is currently available (PDB ID: 2JRZ). Also, in our previous work, a model of ARID‐DNA complex has been generated. The presence of DNA provides constrains of how ARID interacts with the rest of KDM5C domains.…”

“…In our previous work, we generated the 3D structure of ARID‐DNA complex . Here, we took advantage of our previous work and included the DNA in the KDM5C quaternary structure model discussed above.…”

“…(A)]. Our previous evolutionary conservation study showed that the N‐terminal of the KDM5C ARID domain is the most highly conserved region, indicating its essential function for KDM5C protein and thus implicating its involvement in some important interactions. There exists an interface of the ARID domain in which the domain binds the DNA.…”

“…The function of JmjC domain is to specifically demethylate di‐ and trimethylated lysine 4 on histone 3 . The KDM5C acts as a transcriptional repressor and many mutations in the KDM5C gene has been shown to cause X‐linked mental retardation (XLMR) and the syndromic Claes‐Jensen‐type disease . Most of disease‐causing mutations are located on JmjC domain, ZF domain (C5HC2 zinc finger domain) and inter‐domain regions.…”

“…The first experimental structure of one of the KDM5C domains is the solution structure of ARID domain, released in 2007 . In the past, we used it to generate a 3D model of the ARID‐DNA complex . Very recently, the 3D structure of part of the human KDM5C protein (JmjN, JmjC and ZF domains) was released .…”