Protection of telomere 1 (POT1) is a key component of
shelterin complex, essential for maintaining telomere length and its regulation. It consists of N-terminal domain (residues 1-299), which interacts with telomeric ssDNA, and the C-terminal domain (residues 320-634) that binds to the
tripeptidyl-peptidase I (TPP1). A large number of naturally occurring mutations in the POT1 gene are associated with
glioma, cardiac
angiosarcoma and cutaneous
familial melanoma (FM). In particular, Q94E mutation disrupts the interaction of POT1 with telomeric
DNA which subsequently enhances telomere uncapping and elongation and promotes the development of cutaneous
familial melanoma. To understand the underlying mechanism of
familial melanoma developed by Q94E-mutation, we have performed extensive structure analysis of WT and
mutant protein followed by molecular dynamics simulations. Q94E mutation causes a dramatic change in the structure and stability of POT1
protein. A considerable decrease in the flexibility, fluctuation and
solvent accessibility of Q94E was observed in comparison to the WT, indicating overall destabilization of
protein. Essential dynamics and Anisotropic Network Mode analysis have quantified a significant change in direction and magnitude of conformational motion in Q94E mutant compared to WT. A significant loss of frustration due to Q94E mutation was also observed. Our findings indicate the loss of protein stability and dynamics of POT1
protein by Q94E mutation may be associated with the
familial melanoma. AbbreviationsANManisotropic network modeEDessential dynamicsFMfamilial melanomaMDmolecular dynamicsPOT1protection of telomere 1Rgradius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationsSASAsolvent accessible surface areaSIFTsorting Intolerant from TolerantTPP1tripeptidyl-peptidase IWTwild typeCommunicated by Ramaswamy H. Sarma.