Investigation of conformational dynamics of Tyr89Cys mutation in protection of telomeres 1 gene associated with familial melanoma.

Publication date: Dec 17, 2019

Protection of telomeres 1 (POT1) is a component of the shelterin complex which is crucial for the regulation of telomere length and maintenance. Many naturally occurring mutations in the POT1 gene have been found to be associated with cardiac angiosarcoma, glioma, familial melanoma, and chronic lymphocytic leukemia. In particular, Y89C is a naturally occurring mutation of POT1, responsible for familial melanoma, and the molecular basis of this mutation is unexplored. In this study, we have extensively analyzed the structure of WT and Y89C mutants of POT1 to see the change in the conformational dynamics, free energy landscape, molecular motions and configurational frustration using molecular dynamics (MD) and other bioinformatics approaches. Y89C mutation shows a significant in the backbone orientation, compactness, residual fluctuation, solvent accessibility, and hydrogen bonding, suggesting an overall destabilization of protein structure. In addition, essential dynamics, conformational, magnitude and direction of motion and frustration analysis further suggesting the structural loss in POT1 due to Y89C mutation. Free energy landscape analysis also indicates the presence of a single well-defined free-energy minima in case of WT compared to compare to multiple wells defined free energy minima observed in Y89C, clearly suggesting that this mutation leads to reduce the stability of POT1. This study possibly provides a valuable path to understand the molecular basis of Y89C-mediated development of cancer.

Amir, M., Ahamad, S., Mohammad, T., Jairajpuri, D.S., Hasan, G.M., Dohare, R., Islam, A., Ahmad, F., and Hassan, M.I. Investigation of conformational dynamics of Tyr89Cys mutation in protection of telomeres 1 gene associated with familial melanoma. 25183. 2019 J Biomol Struct Dyn.

Concepts Keywords
Accessibility Energy landscape presence
Angiosarcoma Free energy minima
Cancer Leukemia
Chronic Lymphocytic Leukemia Branches of biology
Compactness Natural sciences
Dyn Telomeres
Free Energy Chromosomes
Glioma Molecular biology
Hydrogen Bonding POT1
Magnitude Shelterin
Melanoma Melanoma
Molecular Dynamics Conformational isomerism
Mutants Molecular dynamics
Mutation Simulation


Type Source Name
pathway KEGG Melanoma
disease MESH melanoma
disease MESH angiosarcoma
disease MESH glioma
pathway KEGG Glioma
disease MESH multiple
disease MESH development
disease MESH cancer


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