In silico mutational analysis to identify the role and pathogenicity of BCL-w missense variants

Abstract

Background Intrinsic pathway of apoptosis is generally mediated by BCL-2 (B cell lymphoma 2) family of proteins; they either induce or inhibit the apoptosis. Overexpression of BCL-2 in cancer cell may lead to delay in apoptosis. BCL-w is the pro-survival member of the BCL-2 family. BCL2L2 gene is present on chromosome number 14 in humans, and it encodes BCL-w protein; BCL-w protein is 193 amino acids residues in length. Interactions among the BCL-2 proteins are very specific. The fate of cell is determined by the ratio of pro-apoptotic proteins to pro-survival proteins. BCL-w promotes cell survival. Studies suggested that overexpression of BCL-w protein is associated with many cancers including DLBCL, BL, colorectal cancers, gastric cancers, and many more. The cause of overexpression is translocations or gene amplification which will subsequently result in cancerous activity. Process For in-silico analysis, BCL2L2 gene was retrieved from UniProt (UniProt ID: Q92843). 54 missense variants have been collected in BCL-w proteins from COSMIC database. Different tools were used to detect the deleteriousness of the variants. Result In silico mutational study reveals how the non-synonymous mutations directly affect the protein’s native structure and its function. Variant mutational analysis with PolyPhen-2 revealed that out of 55 variants, 28 of the missense mutations was probably damaging with a score ranging from 0.9 to 1, while 24 variants were benign with a score ranging from 0 to 0.4. Conclusions This in silico work aims to determine how missense mutations in BCL-w protein affect the activity of the protein, the stability of the protein, and to determine the pathogenicity of the variants. Prediction of pathogenicity of variants will reveal if the missense mutation has a damaging effect on the native structure of protein or not. Prediction of protein stability will reveal whether the mutation has a stabilizing or destabilizing effect on the protein.

Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context

“…BCL-W protein is typically located on the mitochondria's outer membrane. The BCL-W protein has nine helices, flanked by amphipathic helices α1, α2, α3, α4, α6, α7, α8, and α9, and a central hydrophobic groove created by a helix, α5 [126].…”

“…BCL-W also regulates the morphogenesis of mitochondria and has been linked to the development of dendrites. Additionally, increased levels of BCL-W cause neurological disorders such as Alzheimer's disease and Parkinson's disease [126]. The overexpression of BCL-W in diffuse large B cell lymphoma was associated with poor patient survival.…”

“…Significantly higher BCL-W mRNA levels are found in breast cancer patients. Cancer of the urinary system has been profoundly impacted by BCL-W. Hepatocellular carcinoma (HCC), leiomyosarcomas, prostate cancer, cervical cancer, and prostate cancer are all linked to overexpression of BCL-W [126]. The BCL-W expression is abnormally high in samples from patients with Hodgkin lymphoma, Burkitt lymphoma (BL), and diffuse large B-cell lymphoma (DLBCL).…”