title: Structural mutation analysis of PTEN and its genotype-phenotype correlations in endometriosis and cancer.
abstract: The phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene encodes a tumor suppressor phosphatase that has recently been found to be frequently mutated in patients with endometriosis, endometrial cancer and ovarian cancer. Here, we present the first computational analysis of 13 somatic missense PTEN mutations associated with these phenotypes. We found that a majority of the mutations are associated in conserved positions within the active site and are clustered within the signature motif, which contain residues that play a crucial role in loop conformation and are essential for catalysis. In silico analyses were utilized to identify the putative effects of these mutations. In addition, coarse-grained models of both wild-type (WT) PTEN and mutants were constructed using elastic network models to explore the interplay of the structural and global dynamic effects that the mutations have on the relationship between genotype and phenotype. The effects of the mutations reveal that the local structure and interactions affect polarity, protein structure stability, electrostatic surface potential, and global dynamics of the protein. Our results offer new insight into the role in which PTEN missense mutations contribute to the molecular mechanism and genotypic-phenotypic correlation of endometriosis, endometrial cancer, and ovarian cancer. Proteins 2016; 84:1625-1643. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77204-5001.
authors.forename: Iris N
authors.identifier: 0000-0001-5560-8871
authors.initials: IN
authors.lastname: Smith
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77204-5001. jbriggs@uh.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Briggs
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D000072417:Protein Domains; D055550:Protein Stability; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D055672:Static Electricity
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PTEN; anisotropic network model; endometrial cancer; endometriosis; genotype-phenotype; global dynamics; mutation; ovarian cancer; protein structure stability