Molecular dynamic simulation of mutated β‑catenin in solid pseudopapillary neoplasia of the pancreas

Tipmanee,Varomyalin; Pattaranggoon,Nawanwat  C.; Kanjanapradit,Kanet; Saetang,Jirakrit; Sangkhathat,Surasak

doi:10.3892/ol.2018.8490

Molecular dynamic simulation of mutated β‑catenin in solid pseudopapillary neoplasia of the pancreas

Authors:
- Varomyalin Tipmanee
- Nawanwat C. Pattaranggoon
- Kanet Kanjanapradit
- Jirakrit Saetang
- Surasak Sangkhathat
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Affiliations: Department of Biomedical Science, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand, Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand
Published online on: April 13, 2018 https://doi.org/10.3892/ol.2018.8490
Pages: 9167-9173
Copyright: © Tipmanee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Solid pseudopapillary neoplasia of the pancreas (SPN) is a rare pancreatic neoplasm that frequently harbors mutations in catenin β1 (CTNNB1, encoding β‑catenin) as a part of its molecular pathogenesis. Mutations to CTNNB1 reported in SPN usually occur at the serine/threonine phosphorylation sites, including codons 33, 37 and 41, and the flanking residues of codon 33. On analysis of 3 cases of SPN, mutations to CTNNB1 were detected in codon 32 (D32A and D32Y). As this residue, aspartic acid, is not a direct phosphorylation site of the protein, molecular modeling tools were used to predict the influence of these mutations on the protein structure of β‑catenin. A total of three MD simulations (wild‑type, D32A, and D32Y) were performed to visualize the conformations of β‑catenin under in vivo, aqueous‑phase conditions at 37˚C. In the wild‑type protein, the secondary structure of residues P16‑H28 remained helical; we therefore hypothesized that the helical structure of this protein fragment (residues M11‑G50) was necessary for phosphorylation of S33 phosphorylation. The loss of the secondary structure in P16‑H28 was observed in D32A, losing its helical structure and becoming a turn; however, in the D32Y mutant, the helical structure remained. The present demonstrated that structural changes in the mutated β‑catenin protein at D32 could potentially explain the mechanism behind its defective phosphorylation in the pathogenesis of SPN.

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