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

Abstract

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 mutant 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 change in the backbone orientation, compactness, residual fluctuation, solvent accessibility, and hydrogen bonding, suggesting an overall destabilization of the protein structure. Besides, essential dynamics, conformation, magnitude, 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 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 familial melanoma.

Communicated by Ramaswamy H. Sarma

Keywords:

• OB folds protein
• molecular dynamics simulation
• protection of telomere 1
• shelterin complex
• mutational landscape analysis
• FEL analysis

Disclosure statement

Authors declare no conflict of interest.

Additional information

Funding

MA acknowledges the Council of Scientific and Industrial Research, India for the award of senior research fellowship 09/466 (0197)2K18 EMR-7. MIH is thankful to the Indian Council of Medical Research, India and the Department of Science and Technology, Government of India for financial support. FA is thankful to the Indian National Science Academy for the award of Senior Scientist Position.