Impact of non-synonymous mutations on the structure and function of telomeric repeat binding factor 1

Abstract

Telomeric repeat binding factor 1 (TRF1) is one of the major components of the shelterin complex. It directly binds to the telomere and controls its function by regulating the telomerase acting on it. Several variations are reported in the TRF1 gene; some are associated with variety of diseases. Here, we have studied the structural and functional significance of these variations in the TRFH domain of TRF1. We have used cutting-edge computational methods such as SIFT, PolyPhen-2, PROVEAN, Mutation Assessor, mCSM, SDM, STRUM, MAESTRO, and DUET to predict the effects of 124 mutations in the TRFH domain of TRF1. Out of 124 mutations, we have identified 12 deleterious mutations with high confidence based on their prediction. To see the impact of the finally selected mutations on the structure and stability of TRF1, all-atom molecular dynamics (MD) simulations on TRF1-Wild type (WT), L79R and P150R mutants for 200 ns were carried out. A significant conformational change in the structure of the P150R mutant was observed. Our integrated computational study provides a comprehensive understanding of structural changes in TRF1 incurred due to the mutations and subsequent function, leading to the progression of many diseases.

Communicated by Ramaswamy H. Sarma

Keywords:

• Telomeric repeat binding factor
• non-synonymous SNP
• deleterious mutations
• molecular dynamics simulation
• structural genomics
• principal component analysis

Acknowledgments

MIH acknowledges the Indian Council of Medical Research, Government of India, for financial assistance (ISRM/12(22)/2020). The authors sincerely thank the Department of Science and Technology, Government of India for the FIST support (FIST program No. SR/FST/LSII/2020/782). MFA and AH extend their sincere appreciation to the Deanship of Scientific Research at King Saud Universityfor its funding of this research through the Research Group Project No. RGP-150. SK would like to acknowledge NRF and AMR-H3D at UCT for financial assistance and also thankful for CHPC, South Africa, for providing technical support. TM is thankful to the University Grants Commission, India, for the award of Senior Research Fellowship.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work is funded by the Council of Scientific and Industrial Research (Grant No. 27(0368)/20/EMRII).