Computational analysis of the functional and structural impact of the most deleterious missense mutations in the human Protein C.

Abstract

Protein C (PC) is a vitamin K-dependent factor that plays a crucial role in controlling anticoagulant processes and acts as a cytoprotective agent to promote cell survival. Several mutations in human PC are associated with decreased protein production or altered protein structure, resulting in PC deficiency. In this study, we conducted a comprehensive analysis of nonsynonymous single nucleotide polymorphisms in human PC to prioritize and confirm the most high-risk mutations predicted to cause disease. Of the 340 missense mutations obtained from the NCBI database, only 26 were classified as high-risk mutations using various bioinformatic tools. Among these, we identified that 12 mutations reduced the stability of protein, and thereby had the greatest potential to disturb protein structure and function. Molecular dynamics simulations revealed moderate alterations in the structural stability, flexibility, and secondary structural organization of the serine protease domain of human PC for five missense mutations (L305R, W342C, G403R, V420E, and W444C) when compared to the native structure that could maybe influence its interaction with other molecules. Protein-protein interaction analyses demonstrated that the occurrence of these five mutations can affect the regular interaction between PC and activated factor V. Therefore, our findings assume that these mutants can be used in the identification and development of therapeutics for diseases associated with PC dysfunction, although assessment the effect of these mutations need to be proofed in in-vitro.