Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes

Abstract

Individuals with germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN), irrespective of clinical presentation, are diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS confers a high risk of breast, thyroid, and other cancers or autism spectrum disorder (ASD) with macrocephaly. It remains unclear why mutations in one gene can lead to seemingly disparate phenotypes. Thus, we sought to identify differences in ASD vs. cancer-associated germline PTEN missense mutations by investigating putative structural effects induced by each mutation. We utilized a theoretical computational approach combining in silico structural analysis and molecular dynamics (MD) to interrogate 17 selected mutations from our patient population: six mutations were observed in patients with ASD (only), six mutations in patients with PHTS-associated cancer (only), four mutations shared across both phenotypes, and one mutation with both ASD and cancer. We demonstrate structural stability changes where all six cancer-associated mutations showed a global decrease in structural stability and increased dynamics across the domain interface with a proclivity to unfold, mediating a closed (inactive) active site. In contrast, five of the six ASD-associated mutations showed localized destabilization that contribute to the partial opening of the active site. Our results lend insight into distinctive structural effects of germline PTEN mutations associated with PTEN-ASD vs. those associated with PTEN-cancer, potentially aiding in identification of the shared and separate molecular features that contribute to autism or cancer, thus, providing a deeper understanding of genotype-phenotype relationships for germline PTEN mutations.

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

“…21 In a recent pilot study, we sought to identify differences in ASD-versus cancer-associated germline PTEN missense variants in silico by investigating putative structural and conformational dynamics. 22 Five of six ASD-associated variants showed localized destabilization, contributing to the partial opening of the active site, whereas all six cancer-associated variants showed long-range perturbations that decreased structural stability and increased dynamics across the domain interface, mediating a closed active site. 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 Five of six ASD-associated variants showed localized destabilization, contributing to the partial opening of the active site, whereas all six cancer-associated variants showed long-range perturbations that decreased structural stability and increased dynamics across the domain interface, mediating a closed active site. 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.…”

PremPS: Predicting the Effects of Single Mutations on Protein Stability

“…Missense mutations can lead to protein dysfunction by affecting their stabilities and interactions with other biological molecules (2)(3)(4)(5)(6). Several studies have shown that the mutations are deleterious due to decreasing/enhancing the stability of the corresponding protein (7)(8)(9)(10)(11)(12). To quantify the effects on protein stability requires estimating the changes in folding/unfolding Gibbs free energy induced by mutations.…”

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer

“…LINCS L1000(27, 29, 53) (http://amp.pharm.mssm.edu/L1000CDS2/#/index) comprises a collection of 230,556 gene expression profiles of cancer cell lines perturbed by small molecules and genetic constructs. Here, a subset of 29,157 small molecule perturbations that was included in a custom drug classification partially based on the anatomical therapeutic chemical classification system (ATC) was selected and employed to perform drug set enrichment analyses for each studied condition as previously described in Sanchez et al(51).…”