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.

Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer

“…22 Most notable was the identification of an inter-domain disruption with an increase in dynamics across the phosphatase-C2 domain interface in PTEN, and this disruption was observed in both the c.388C>G (p.Arg130Gly) (cancer only) and c.517C>T (p.Arg173Cys) (shared in individuals with both ASD and cancer) mutations, indicating both residue positions play a role in inter-residue signal propagation and are crucial to structural stability. 22,23 These results provide evidence to support the recent identification of pivotal mutational-sites that might serve as key mediating bridges of allosteric communication in PTEN. 24 Allosteric propagation results in communication between distinct sites in the protein structure and takes place through dynamic shifts of conformational ensembles.…”

“…20 The highly conserved active-site loops, despite their obvious central role in catalysis, have been subject to minimal scrutiny in dynamic cross-talk with a possible allosteric regulation site. [22][23][24] However, our RIN analysis highlights how different conformations within the active-site loops mediate long-range interactions between the active site, N-terminal region, ATP-B binding site, CBR3 loop, and the inter-domain region, and thus might play an active role in allostery. In fact, it has been shown that PI(4,5)P 2 binds to N-terminal residues 6-15, thereby inducing an allosteric conformational change that activates PTEN.…”

Loss of phosphatase activity in PTEN (phosphatase and tensin homolog deleted on chromosome ten) results in endometrial carcinoma in humans: An in-silico study

“…Although we cannot reach our goals through our results, we have found some results that conduct follow-up studies to retrieve novel molecular targets. Apart from this, some previous studies (Lee et al, 1999;Walker et al, 2004, Smith andBriggs, 2016) have shown that in the N terminal's active site residues, most of the mutations are seen. Additionally, we indicate H123 position is a strongly mutated residue by SNPs dataset, which also has shown as MMAC site of human PTEN protein sequence by NCBI data.…”

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“…As a gene on chromosome 10q23.3, PTEN is also the second most susceptible gene found in the human tumor after p53 gene (Siddiqui et al, 2016). PTEN gene mutation or deficiency and abnormal protein expression can promote cell proliferation and inhibit cell apoptosis, the expression of PTEN in malignant tumors is negatively correlated with tumor TNM staging, and meantime, the low expression of PTEN is closely related to chemotherapy resistance of breast cancer (Song et al, 2016); (Wu et al, 2016).…”