Prediction of the Effects of Missense Mutations on Human Myeloperoxidase Protein Stability Using In Silico Saturation Mutagenesis

Abstract

Myeloperoxidase (MPO) is a heme peroxidase with microbicidal properties. MPO plays a role in the host’s innate immunity by producing reactive oxygen species inside the cell against foreign organisms. However, there is little functional evidence linking missense mutations to human diseases. We utilized in silico saturation mutagenesis to generate and analyze the effects of 10,811 potential missense mutations on MPO stability. Our results showed that ~71% of the potential missense mutations destabilize MPO, and ~8% stabilize the MPO protein. We showed that G402W, G402Y, G361W, G402F, and G655Y would have the highest destabilizing effect on MPO. Meanwhile, D264L, G501M, D264H, D264M, and G501L have the highest stabilization effect on the MPO protein. Our computational tool prediction showed the destabilizing effects in 13 out of 14 MPO missense mutations that cause diseases in humans. We also analyzed putative post-translational modification (PTM) sites on the MPO protein and mapped the PTM sites to disease-associated missense mutations for further analysis. Our analysis showed that R327H associated with frontotemporal dementia and R548W causing generalized pustular psoriasis are near these PTM sites. Our results will aid further research into MPO as a biomarker for human complex diseases and a candidate for drug target discovery.

A Computational Approach: The Functional Effects of Thyroid Peroxidase Variants in Thyroid Cancer and Genetic Disorders

“…29 In our previous study, we highlighted the reliability of our approach to identifying missense mutations in the MPO protein. 30 In the case of TPO, chemiluminescence immunoassay and other experimental assays were used to identify some thyroid-related diseases. However, the experimental assay requires many samples, and it is tedious, slow, and labor-intensive.…”

Effect of CTSS non-synonymous mutations on litter size in Qianbei Ma goats

“…The mutation had a neutral effect on protein function; but, interestingly, the p.S161F mutation increased the stability of the protein, and the p.N219Y mutation decreased the stability of the protein. It has been shown that missense mutations that increase protein stability may also alter their function, that more stable proteins are more evolved and that mutations at the p.S161F and p.N219Y loci are consistent with speciation (45)(46)(47). Studies of the secondary and tertiary structures of the protein showed that mutations resulted in a decreased proportion of extended chains and β-turns and an increased proportion of irregular coiling.…”