Abstract
Cancer is one of the world's major causes of mortality, and it plays a most important role in the world's declining life expectancy. F-box and WD-40 domain protein 7 (FBXW7), a typical participant of the F-box family of proteins, has been considered as an anti-tumor protein and one of the maximum deregulated ubiquitin-proteasome system proteins in uterine carcinosarcoma, endometrial clear cell carcinoma and cervical carcinoma with the greatest prevalence of alterations. FBXW7 variants with known clinical significance, as well as non-synonymous single nucleotide polymorphisms (nsSNPs) in the F-Box and WD40 domains, were evaluated using functionality prediction web resources. Upon analysing the seventy-three deleterious nsSNP's impact on protein stability and function, we identified that forty-one nsSNPs of WD40 domain and three of F-Box domain imply decreased stability of the FBXW7 structure. Next to TP53 and PTEN, FBXW7 was reported with the highest percentage of arginine substitution among mutations related to cancer. The current research concentrated on two arginine residue locations (Arg465, Arg505) within the WD40-repeat domain, which is vital for substrate binding. Computational analysis revealed significant deviation in stability and structural configuration of mutants R505L, R465H, R465P, R505G, R505C, R465C, R505S and R505L structures. Protein-protein interaction network of FBXW7 populated with promising hub proteins NOTCH1, c-Myc, CCNE1, STYX, KLG5, SREB1, NFKB2, SKP1 and CUL1; thus, alteration in the FBXW7 leads to aberration in their signalling pathways as well as their substrate binding ability makes this protein as attractive target for personalized therapeutic intervention.
Highlights
Cancer is one of the prominent reasons for mortality globally, including increased life expectancy
Protein– protein interaction network of F-box and WD-40 domain protein 7 (FBXW7) populated with promising hub proteins NOTCH1, c-Myc, CCNE1, STYX, KLG5, SREB1, NFKB2, SKP1, CUL1, alteration in the FBXW7 leads to aberration in their signalling pathways as well as their substrate binding ability makes this protein as attractive target for personalized therapeutic intervention
To have an overview of FBXw7 expression in different solid tumours, we analysed its expression in samples from the TCGA, which revealed that FBXw7 is coupled with differential expression as well as cervical, endometrial, and ovarian cancer in women (Fig. 1)
Summary
Cancer is one of the prominent reasons for mortality globally, including increased life expectancy. Mutations assist the oncogenic substrate accumulation and direct the resistance phenotype of T-ALL cell lines in response to a gamma-secretase inhibitor [14] These data show that FBXW7 could be exploited as a potential target for overcoming chemo resistance in a variety of cancers, not merely as a biomarker for predicting chemotherapy effectiveness. We evaluated sequence and structure-based bioinformatics protein stability indicator techniques to anticipate the effect of the mutation on FBXW7 protein stability to get extensive structural and mechanistic insight of wild type to mutant FBXW7 protein structures The results of these computational investigations suggest that structural changes caused by missense mutations may affect FBXW7's functional activity, which will aid in the development of inhibitors
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