Computational investigation of pathogenic nsSNPs in CEP63 protein

Centrosomes are central regulators of mitosis that are often amplified in cancer cells. Centrosomal protein of 63 kDa (CEP63) is a centrosomal protein that has an effective role in mitotic spindle assembly and cell cycle regulation. Genetic alterations in CEP63 coding gene has been widely studied for inducing aneuploidy and solid tumors in humans. The nonsynonymous single nucleotide polymorphisms (nsSNPs) are a genetic variant resulting in amino acid substitution and are reported in a wide range of human diseases. Here we report one new SNP (rs112926188) in a CEP63 coding region that can potentially disrupt the structure and basic functionality of a CEP63 protein. We used extensive functional and structural level analyses of an available SNP in a CEP63 coding gene. Furthermore the disease-association analysis was carried out to examine the possible pathogenic variant among the available dataset. To understand atomic arrangement in 3D space, native and pathogenic mutant structures were modeled. Molecular dynamics simulations were performed to understand structural consequences of prioritized deleterious mutation. Our analysis showed that rs112926188 allele substituting proline at the 61st residue position (L61P) produced more flexibility in 3D space. Moreover the flexible nature of mutant L61P was validated by a hydrogen bond network. This nature of mutant L61P CEP63 may restrict the recruitment of essential centrosomal proteins to their respective location and may play an active role in inducing aneuploidy.

► Effectiveness of computational platform in pathogenic allele prediction ► L61P mutation in CEP63 prioritized to be deleterious and disease associated ► Change in dynamic behavior of L61P mutant protein as compared to native ► Loss of mutant protein conformation, NHbond formation and protein stability ► Structural consequences of a point mutation in CEP63