Impact of Gln94Glu mutation on the structure and function of protection of telomere 1, a cause of cutaneous familial melanoma

Abstract

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.

Keywords: Protection of telomere 1; molecular dynamics simulation; mutation; protein stability; shelterin complex; structural genomics.