Abstract
Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD) simulation that demonstrated the role of the mutation in protein structure destability and affecting its internal dynamics. The findings of this study are believed to open doors to investigate the biological relevance of the mutations and drugability potential of the protein.
Highlights
Pirin (PIR) protein is considered highly conserved in both prokaryotic and eukaryotic organisms; its biological functions are poorly described (Dunwell et al, 2001; Pang et al, 2004)
Previous studies reported the overexpression of PIR in different neoplastic transformation and its role in the enhancement of tumor formation due to inducing the expression of Bcl3 by forming the ternary complex with protooncogenes Bcl3 and NF-kB (Zhu et al, 2003; Massoumi et al, 2009)
It has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level (Suleman et al, 2019)
Summary
Pirin (PIR) protein is considered highly conserved in both prokaryotic and eukaryotic organisms; its biological functions are poorly described (Dunwell et al, 2001; Pang et al, 2004). It has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level (Suleman et al, 2019). It was a significant breakthrough in unveiling the hidden function of PIR in the field of cancer. This study is the first extensive in silico analysis of the PIR gene that can narrow down the candidate mutations for further validation and targeting for therapeutic purposes
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