Influence of PRKCE non-synonymous variants on protein dynamics and functionality

Khan, Khushbukhat; Shah, Hania; Rehman, Areeba; Badshah, Yasmin; Ashraf, Naeem Mahmood; Shabbir, Maria

doi:10.1093/hmg/ddac029

Cited by 14 publications

(16 citation statements)

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“…Its aberrant expression is particularly reported in cancers such as gall bladder cancer, prostate cancer, brain tumours, and lung cancer [ 66–70 ]. Recently, the role of non-synonymous variants in affecting the function and structure of PKCε protein was evaluated through more than thirty bioinformatics tools [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, extensive In silico analysis of non-synonymous variants in PRKCE has been performed, revealing the presence of non-synonymous polymorphic variants in different regions of this protein, resulting in altered proteins structure and functions along with altered structural dynamics, affecting its molecular interactions and mode of activation [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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PRKCE non-coding variants influence on transcription as well as translation of its gene

et al. 2022

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Untranslated regions of the gene play a crucial role in gene expression regulation at mRNA and protein levels. Mutations at UTRs impact expression by altering transcription factor binding, transcriptional/translational efficacy, miRNA-mediated gene regulation, mRNA secondary structure, ribosomal translocation, and stability. PKCε, a serine/threonine kinase, is aberrantly expressed in numerous diseases such as cardiovascular disorders, neurological disorders, and cancers; its probable cause is unknown. Therefore, in the current study, the influence of PRKCE 5’-and 3'UTR variants was explored for their potential impact on its transcription and translation through several bioinformatics approaches. UTR variants data was obtained through different databases and initially evaluated for their regulatory function. Variants with regulatory function were then studied for their effect on PRKCE binding with transcription factors (TF) and miRNAs, as well as their impact on mRNA secondary structure. Study outcomes indicated the regulatory function of 73 5'UTR and 17 3'UTR variants out of 376. 5'UTR variants introduced AP1 binding sites and promoted the PRKCE transcription. Four 3'UTR variants introduced a circular secondary structure, increasing PRKCE translational efficacy. A region in 5'UTR position 45,651,564 to 45,651,644 was found where variants readily influenced the miRNA-PRKCE mRNA binding. The study further highlighted a PKCε-regulated feedback loop mechanism that induces the activity of TFs, promoting its gene transcription. The study provides foundations for experimentation to understand these variants’ role in diseases. These variants can also serve as the genetic markers for different diseases’ diagnoses after validation at the cell and population levels.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PRKCE non-coding variants influence on transcription as well as translation of its gene

et al. 2022

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“…Recently, the pathogenic variants of PKC family members nPKCε and aPKCι were predicted through bioinformatics tools (43). Through in silico analysis, PKCι variants rs1199520604 and rs1197750201 were sorted as the most deleterious variant.…”

Section: Discussionmentioning

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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“…Altered amino acid sequence may affect the stability of the protein. To analyze the effect of nsSNP on protein stability, five different web-based tools were used; i.e., I-Mutant [ 24 ], MUpro [ 25 ], DynaMut [ 26 ], mCSM [ 27 ] and SDM [ 27 ].The amino acid sequence in FASTA format was used as input for both I-Mutant and MUpro.ProjectHOPE [ 25 ] was also used, with the amino acid sequence of PKC gamma used as input. Substitution and amino acid positions were selected in the subsequent steps.…”

Section: Methodsmentioning

confidence: 99%

“…Molecular dynamic simulation for both wild type and mutated proteins was carried out via GROMACS software [ 24 ] to analyze the impact of residue change at different time scale in dynamic environment. Wild and mutated protein’s PDB (Program Database) were used as initial input in the simulation.…”

Section: Methodsmentioning

confidence: 99%

Analyzing PKC Gamma (+ 19,506 A/G) polymorphism as a promising genetic marker for HCV-induced hepatocellular carcinoma

et al. 2022

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Background HCC is a major health concern worldwide. PKC gamma, a member of the conventional PKC subclass, is involved in many cancer types, but the protein has received little attention in the context of single nucleotide polymorphisms and HCC. Therefore, the study aims to investigate the association of PKC gamma missense SNP with HCV-induced hepatocellular carcinoma. Methods The PKC gamma nsSNPs were retrieved from the ENSEMBL genome browser and the deleterious nsSNPs were filtered out through involvingPredictSNP2, CADD, DANN, FATHMM, FunSeq2 and GWAVA. Among the filtered nsSNPs, nsSNP rs1331262028 was identified to be the most pathogenic one. Through involving I-TASSER, ProjectHOPE, I-Mutant, MUpro, mCSM, SDM, DynaMut and MutPred, the influence of SNP rs1331262028 on protein structure, function and stability was estimated. A molecular Dynamic simulation was run to determine the conformational changes in mutant protein structure compared to wild. The blood samples were collected for genotyping analysis and for assessing ALT levels in the blood. Results The study identified for the first time an SNP (rs1331262028) of PRKCG to strongly decrease protein stability and induce HCC. The RMSD, RMSF, and Rg values of mutant and wild types found were significantly different. Based on OR and RR values of 5.194 and 2.287, respectively, genotype analysis revealed a higher correlation between the SNP homozygous wild Typeform, AA, and the disease while patients with genotype AG have higher viral load. Conclusion Outcomes of the current study delineated PKC gamma SNP rs1331262028 as a genetic marker for HCV-induced HCC that could facilitate disease management after further validation.

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Influence of PRKCE non-synonymous variants on protein dynamics and functionality

Cited by 14 publications

References 100 publications

PRKCE non-coding variants influence on transcription as well as translation of its gene

PRKCE non-coding variants influence on transcription as well as translation of its gene

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

Analyzing PKC Gamma (+ 19,506 A/G) polymorphism as a promising genetic marker for HCV-induced hepatocellular carcinoma

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