<i>In silico</i> and <i>in vitro</i> mutational analysis to investigate the structure and pathogenicity of <i>POT1</i> missense variants.

ABSTRACT: We performed an initial assessment of 24 missense POT1variants using variant effect predictors (VEPs) followed by an extensive molecular dynamics (MD) simulations of 14 selected variants: N-terminal: I115T, Y223C, D224N, M251V, H266Q, and S270N, C-terminal: A364E, P371T, T416A, S421L, A532P, L538V, P601L, and Q623H for the unbound state and bound state with telomeric ssDNA (N-terminal) or TPP1-PBD (C-terminal). Wet-lab validations using electrophoretic mobility shift assay (EMSA), telomere dysfunction-induced foci (TIF) formation analysis and coimmunoprecipitation were done to further explore the functional impacts. Initial assessment included VEPs, FoldX, and I-Mutant2.0 followed by MD analysis, which revealed structural instability and reduction in associated binding efficiency in

SUBMITTER: Nguyen T 

PROVIDER: S-EPMC12429947 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature