Tryptophan to Glycine mutation in the position 116 leads to protein aggregation and decreases the stability of the LITAF protein

Abstract

Mutations in the gene-encoding vesicle lipopolysaccharide-induced tumor necrosis factor (LITAF) protein cause Charcot–Marie–Tooth type 1C (CMT1C) disease, a neurological disorder. The LITAF gene is mapped to chromosome number 16 and can be found at cytogenetic location 16p13 of the chromosome. CMT1C-linked small integral membrane protein of lysosome/late endosome mutants are loss-of-function mutants that act in a dominant negative manner to impair endosomal trafficking, leading to prolonged extracellular signal-regulated kinases 1/2 signaling downstream of ErbB activation. Mutation W116G in the LITAF decreases the stability of the protein and also interrupts the functioning of gene. We have analyzed the single nucleotide polymorphism (SNP) results of 28 nsSNPs obtained from dbSNP. We also carried out multiple molecular dynamics simulations of 200 ns and obtained results of root-mean-square deviation, root-mean-square fluctuation, radius of gyration, solvent-accessible surface area, H-bond, and principal component analysis to check and prove the stability of both the wild type and the mutant. The protein was then checked for its aggregation and the results showed loss of helix. The loss of helix leads to the instability of the protein.

Keywords:

• Charcot–Marie–Tooth disease
• lipopolysaccharide-induced TNF factor protein
• SNP analysis
• molecular dynamics simulations
• protein aggregation

Acknowledgments

RGS thanks ICMR for the Senior Research Fellowship. The authors would also like to thank the management of VIT University for providing the necessary facilities to carry out this research project.

Additional information

Funding

Funding. SR and AA gratefully acknowledge the Indian Council of Medical Research (ICMR), Government of India Agency for the research grant [IRIS ID: 2014-0099].