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J Biomol Struct Dyn. 2019 Apr;37(7):1766-1782. doi: 10.1080/07391102.2018.1465854. Epub 2018 May 14.

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

Smith IN1, Thacker S1,2, Jaini R1,3,2, Eng C1,4,5,3,2.

Author information

1
a Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , Cleveland , OH , USA.
2
e Cleveland Clinic Lerner College of Medicine , Cleveland , OH , USA.
3
d Germline High Risk Cancer Focus Group , Comprehensive Cancer Center, Case Western Reserve University School of Medicine , Cleveland , OH , USA.
4
b Taussig Cancer Institute, Cleveland Clinic , Cleveland , OH , USA.
5
c Department of Genetics and Genome Sciences, Case Westren Reserve University School of Medicine , Cleveland , OH , USA.

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.

KEYWORDS:

ASD: Autism spectrum disorder; ATP: Adenosine triphosphate; ENCoM: Elastic network contact model; GROMACS: Groningen machine for chemical simulations; LINCS: Linear constraint solver; MD: Molecular dynamics; NMA: Normal mode analysis; PCA: Principal component analysis; PDB: Protein data bank; PHTS: hamartoma tumor syndrome; PIP: Phosphatidylinositol-3,4,5-triphosphate; PIP: Phosphatidylinositol-4,5-biphosphate; PME: Particle mesh Ewald; PTEN; PTEN: Phosphatase and tensin homolog deleted on chromosome ten; RMSD: Root mean square deviation; Rg: Radius of gyration; VMD: Visual Molecular Dynamics; WT: Wild-type; autism; cancer; molecular dynamics simulations; poly(Glu-pTyr): Polymers of glutamate and tyrosine, 1:1 ratio; protein structure stability

PMID:
29663862
PMCID:
PMC6235728
[Available on 2020-04-01]
DOI:
10.1080/07391102.2018.1465854

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