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.