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

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. AbbreviationsANM

anisotropic network mode

ED

essential dynamics

FM

familial melanoma

MD

molecular dynamics

POT1

protection of telomere 1

Rg

radius of gyration

RMSD

root-mean-square deviation

RMSF

root-mean-square fluctuations

SASA

solvent accessible surface area

SIFT

sorting Intolerant from Tolerant

TPP1

tripeptidyl-peptidase I

WT

wild type

anisotropic network mode

essential dynamics

familial melanoma

molecular dynamics

protection of telomere 1

radius of gyration

root-mean-square deviation

root-mean-square fluctuations

solvent accessible surface area

sorting Intolerant from Tolerant

tripeptidyl-peptidase I

wild type

Communicated by Ramaswamy H. Sarma