Novel mutation predicted to disrupt SGOL1 protein function

Abstract

Cell cycle alterations are the major cause of cancers in human. The proper segregation of sister chromatids during the cell division process defines the fate of daughter cells which is efficiently maintained by various proteomic complexes and signaling cascades. Shugosin (SGOL1) is one among those proteins which are required for phosphatise 2A protein (PP2A) localization to centromeres during division. This localization actively manages the adherence of sister chromatids at the centromeric region until the checkpoint signals are received. Wide evidences of SGOL1 genomic variants have been studied for their correlation with chromosomal instability and chromatid segregation errors. Here we used computational methods to prioritize the Single Nucleotide Polymorphism’s (SNP’s) capable of disrupting the normal functionality of SGOL1 protein. L54Q, a mutation predicted as deleterious in this study was found to be located in N-terminal coiled coil domain which is effectively involved in the proper localization of PP2A to centromere. We further examined the effect of this mutation over the translational efficiency of the SGOL1 coding gene. Our analysis revealed major structural consequences of mutation over folding conformation of the 3rd exon. Further we carried molecular dynamic simulations to unravel the structural variations induced by this mutation in SGOL1 N-terminal coiled coil domain. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), H-Bond scores further supported our result. The result obtained in our study will provide a landmark to future research in understanding genotype-phenotype association of damaging non-synonymous SNPs (nsSNPs) in several other centromere proteins as done in SGOL1 and will be helpful to forecast their role in chromosomal instabilities and solid tumor formation.

Keywords: SGOL1; Molecular Dynamics Simulation; Gromacs; PhD-SNP; SIFT; Polyphen; MutPred

The Egyptian Journal of Medical Human Genetics (2013) 14, 149–155