Impact of deleterious missense PRKCI variants on structural and functional dynamics of protein

Shah, Hania; Khan, Khushbukhat; Khan, Naila Zaman; Badshah, Yasmin; Ashraf, Naeem Mahmood; Shabbir, Maria

doi:10.1038/s41598-022-07526-4

Cited by 7 publications

(7 citation statements)

References 57 publications

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“…The structure of CTLA4 and its mutants were predicted via I-TASSER. The nsSNPs directly influence the structure and hence function of a protein therefore, the effect of nsSNPs on structure of CTLA4 was assessed 47 . It was observed that the predicted mutant structures of CTLA4 have significantly distinguished RMSD values than the wild type and may compromise the structural integrity of the protein 47 .…”

Section: Discussionmentioning

confidence: 99%

Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene

Irfan¹,

Iqbal²,

Hashmi³

et al. 2022

Sci Rep

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The CTLA4 receptor is an immune checkpoint involved in the downregulation of T cells. Polymorphisms in this gene have been found to be associated with different diseases like rheumatoid arthritis, autosomal dominant immune dysregulation syndrome, juvenile idiopathic arthritis and autoimmune Addison's disease. Therefore, the identification of polymorphisms that have an effect on the structure and function of CTLA4 gene is important. Here we identified the most damaging missense or non-synonymous SNPs (nsSNPs) that might be crucial for the structure and function of CTLA4 using different bioinformatics tools. These in silico tools included SIFT, PROVEAN, PhD-SNP, PolyPhen-2 followed by MutPred2, I-Mutant 2.0 and ConSurf. The protein structures were predicted using Phyre2 and I-TASSER, while the gene–gene interactions were predicted by GeneMANIA and STRING. Our study identified three damaging missense SNPs rs1553657429, rs1559591863 and rs778534474 in coding region of CTLA4 gene. Among these SNPs the rs1553657429 showed a loss of potential phosphorylation site and was found to be highly conserved. The prediction of gene–gene interaction showed the interaction of CTlA4 with other genes and its importance in different pathways. This investigation of damaging nsSNPs can be considered in future while studying CTLA4 related diseases and can be of great importance in precision medicine.

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Section: Discussionmentioning

confidence: 99%

Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene

Irfan¹,

Iqbal²,

Hashmi³

et al. 2022

Sci Rep

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“…In a study conducted in 2022, different PKCι missense variants were evaluated for pathogenicity and potential for carcinogenesis [ 9 ]. Out of those variants, two were present in the PB1 domain were selected for this particular study because the function of the PB1 domain is essential for the interaction of PKCι with Par-6 during cellular polarity.…”

Section: Methodsmentioning

confidence: 99%

Possible prognostic impact of PKCι genetic variants in prostate cancer

Hafeez,

Shabbir,

Khan

et al. 2024

Cancer Cell Int

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Background Single nucleotide polymorphisms (SNPs) have been linked with prostate cancer (PCa) and have shown potential as prognostic markers for advanced stages. Loss of function mutations in PKCι have been linked with increased risk of malignancy by enhancing tumor cell motility and invasion. We have evaluated the impact of two coding region SNPs on the PKCι gene (PRKCI) and their prognostic potential. Methods Genotypic association of non-synonymous PKCι SNPs rs1197750201 and rs1199520604 with PCa was determined through tetra-ARMS PCR. PKCι was docked with interacting partner Par-6 to determine the effect of these variants on PKCι binding capabilities. Molecular dynamic simulations of PKCι docked with Par-6 were performed to determine variant effects on PKCι protein interactions. The possible impact of changes in PKCι protein interactions on epithelial cell polarity was hypothesized. Results PKCι rs1199520604 mutant genotype TT showed association with PCa (p = 0.0055), while rs1197750201 mutant genotype AA also showed significant association with PCa (P = 0.0006). The binding interaction of PKCι with Par-6 was altered for both variants, with changes in Van der Waals energy and electrostatic energy of docked structures. Conclusion Genotypic analysis of two non-synonymous PKCι variants in association with PCa prognosis was performed. Both variants in the PB1 domain showed potential as a prognostic marker for PCa. In silico analysis of the effect of the variants on PKCι protein interactions indicated they may be involved in PCa progression through aberration of epithelial cell polarity pathways.

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“…Furthermore, pathogenic variants of PKC (rs1199520604, rs1197750201) were also investigated for their association with breast cancer pathogenesis. The pathogenicity of these variants was determined in the previous study using several bioinformatics approaches (17). The outcomes of this study will facilitate the development of genetic marker that could facilitate in breast early diagnosis and prognosis and could reduce the risk of drug resistance development.…”

Section: Introductionmentioning

confidence: 92%

“…PKC is involved in several carcinogenic processes and its altered expression levels have been reported in various types of cancers (9,18,19). In our previous study, we have scrutinized deleterious polymorphic variants of PKC (17). Out of those, SNPs of the PB1 domain G34W (rs1199520604), and F66Y (rs1197750201) of PKC were selected for the assessment of association with breast cancer.…”

Section: Selection Of Gene and Variants For Arm's Pcrmentioning

confidence: 99%

Association of PKCi variant and its gene expression with breast cancer prognosis

Shah

Khan

Badshah

et al. 2022

Preprint

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Breast cancer is one of the most common causes of fatalities in females globally. Rising cases of drug resistance against existing chemotherapeutics are great problem. To address this issue, there is a need to find appropriate biomarker that could be used to detect cancer at early stages, so drug resistance development can be avoided. Protein Kinase C iota (PKCɩ), an AGC kinase, has an oncogenic role in cancers and its expression and SNPs have been reported to be associated with the cancer development. So, the study aims were to examine the expression of PKCɩ, Protein Kinase B (AKT), Suppressor of cytokine signaling 3 (SOC3), Vascular endothelial growth factor (VEGF), Krupple like factor 3 (KLF3), Tumor protein D52 (TPD52), Hypoxia inducible factor (HIF1α) and microRNA-124 (miR-124) in breast cancer and association of PKCɩ variants (G34W & F66Y) with breast cancer.: Genetic expression assay was performed through real time PCR, whereas the genotypic association of PKCɩ SNPs with breast cancer was accomplished through Tetra-ARMS PCR. The overall expression levels of PKCɩ, AKT, SOC3, VEGF, HIF1α and TPD52 were elevated in patients as compared to control whereas the expression levels of miR-124 and KLF3 were lowered in patients. Positive association of variant G34W (TT) of PKCɩ with breast cancer has been explored while no association of variant F66Y with breast cancer was found. Hence, the results suggest that PKCɩ and related genes can serve as the potential biomarkers for the early-diagnosis and prognosis of breast cancer.

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Impact of deleterious missense PRKCI variants on structural and functional dynamics of protein

Cited by 7 publications

References 57 publications

Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene

Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene

Possible prognostic impact of PKCι genetic variants in prostate cancer

Association of PKCi variant and its gene expression with breast cancer prognosis

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