Understanding Structure and Dynamics of PTEN and its Possible Genotype-Phenotype Correlations in Endometriosis and Cancer
Smith, Iris Nira 1978-
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The phosphatase and tensin homolog deleted on chromosome 10, (PTEN) gene encodes a tumor suppressor phosphatase frequently mutated in various human cancers. Somatic missense mutations of PTEN have recently been found in patients with endometriosis, endometrial cancer, and ovarian cancer. Here we present the first computational analysis of 13 somatic missense PTEN mutations to assess a possible genotype-phenotype correlation in endometriosis and cancer. We posit PTEN’s active site defines a possible mutation-driven allosteric region wherein a subset of mutations correlate with endometriosis, endometrial cancer, and ovarian cancer. Our data suggest that mutations within the active site disrupt the structural stability, electrostatic interaction, global dynamics and the structural communication pathway, likely contributing to the aforementioned phenotypes. Multiple in silico prediction methods were utilized to calculate protein structural stability changes produced by each mutation; decreases in protein structure stability were seen in each mutation with an increase in dynamics across the phosphatase-C2 domain interface of R130G/L/Q and R173C/H mutations. To assess the impact on intrinsic and global dynamics, elastic network models (ENMs) were employed demonstrating changes from wild-type “hinge-bending” to “zipper-like” global motions induced by each mutation. All-atom molecular dynamics (MD) simulations revealed large conformational changes that affect the global dynamics of the active site loops and the CBR3 loop in the C2 domain. Interestingly, mutations G36E/R, C124S, G129R, R130L/Q, R173C/H, and V191A dramatically affected the principal motions of the active site loops and inter-domain interface. Overall, the global dynamics induced by each mutation effects reveal unique long-range perturbations that may impair PTEN’s function. We further investigated structural communication within each mutant system using protein structure network (PSN) analysis and found that R130 and R173 play critical roles in controlling salient communication pathways suggesting a compelling interplay between the two positions involving a potential mutation-driven allosteric interface. The results of this research provide a greater understanding of the mechanistic role of mutated PTEN associated with endometriosis and cancer. It is our hope that these results will aid in a better clinical-molecular classification of the resulting phenotypes allowing for translation into improved diagnostic and therapeutic approaches.