Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India
Abstract Renal cell carcinoma (RCC) is the one of the most fatal and frequent form of urological malignancy worldwide. The von Hippel-Lindau (VHL) tumour suppressor gene is a critical component of the VHL-Cullin2-ElonginB/C (VCB) complex that regulates the ubiquitin-mediated proteasomal degradation...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-95875-1 |
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| author | Srilagna Chatterjee Nirvika Paul Anwesha Das Sarbashri Bank Biswabandhu Bankura Ravi Prakash Yadav Kunal Sarkar Soumen Saha Subhajit Malakar Sunirmal Choudhury Sudakshina Ghosh Madhusudan Das |
| author_facet | Srilagna Chatterjee Nirvika Paul Anwesha Das Sarbashri Bank Biswabandhu Bankura Ravi Prakash Yadav Kunal Sarkar Soumen Saha Subhajit Malakar Sunirmal Choudhury Sudakshina Ghosh Madhusudan Das |
| author_sort | Srilagna Chatterjee |
| collection | DOAJ |
| description | Abstract Renal cell carcinoma (RCC) is the one of the most fatal and frequent form of urological malignancy worldwide. The von Hippel-Lindau (VHL) tumour suppressor gene is a critical component of the VHL-Cullin2-ElonginB/C (VCB) complex that regulates the ubiquitin-mediated proteasomal degradation of proteins with mutations consistently associated with the development of clear cell renal cell carcinoma (ccRCC). Despite extensive investigations conducted worldwide, there is a notable lack of data concerning VHL mutations in sporadic ccRCC patients from India. Our study aimed to investigate the sporadic VHL mutations within the tumours of 210 ccRCC patients without a familial history of VHL disease. We extracted genomic DNA from tumour and adjacent normal tissues, PCR amplified and sequenced the VHL gene. In silico tools were used assess the damaging potential of missense variants on pVHL structure and stability. Protein-protein docking and protein flexibility molecular docking simulation study were employed to study the interaction between wild-type and mutated VHL models with Elongin C. Sequence analysis revealed seven novel missense mutations in patient tumour tissues p.(Val170Phe), p.(Arg69Cys), p.(Phe76Leu), p.(Glu173Asp), p.(Leu201Val), p.(His208Leu), p.(Arg205Pro). I-Mutant 2.0 indicated these mutations reduced pVHL stability (ΔΔG < -0.5 kcal/mol). Protein Flexibility-Molecular Dynamic (MD) Simulation study indicated that mutations weaken the interaction of VHL with Elongin C, with V170F showing the most significant reduction in binding quality and stability. In conclusion, this study introduces novel genetic data from an understudied population and highlights the impact of VHL mutations on its interaction with Elongin C. These findings contribute to our understanding of the molecular basis of VHL-related pathologies and may guide future therapeutic strategies targeting these interactions. |
| format | Article |
| id | doaj-art-e49e1ea996bb42ca8e11b6179a14527b |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
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| spelling | doaj-art-e49e1ea996bb42ca8e11b6179a14527b2025-08-20T02:27:53ZengNature PortfolioScientific Reports2045-23222025-04-0115111610.1038/s41598-025-95875-1Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern IndiaSrilagna Chatterjee0Nirvika Paul1Anwesha Das2Sarbashri Bank3Biswabandhu Bankura4Ravi Prakash Yadav5Kunal Sarkar6Soumen Saha7Subhajit Malakar8Sunirmal Choudhury9Sudakshina Ghosh10Madhusudan Das11Department of Zoology, University of CalcuttaDepartment of Zoology, University of CalcuttaDepartment of Zoology, University of CalcuttaDepartment of Zoology, University of CalcuttaMultidisciplinary Research Unit, Calcutta Medical College and HospitalDepartment of Zoology, University of CalcuttaDepartment of Zoology, University of CalcuttaDepartment of Urology, Calcutta Medical College and HospitalDepartment of Urology, Institute of Postgraduate Medical Education and ResearchDepartment of Urology, Calcutta Medical College and HospitalDepartment of Zoology, Vidyasagar College for WomenDepartment of Zoology, University of CalcuttaAbstract Renal cell carcinoma (RCC) is the one of the most fatal and frequent form of urological malignancy worldwide. The von Hippel-Lindau (VHL) tumour suppressor gene is a critical component of the VHL-Cullin2-ElonginB/C (VCB) complex that regulates the ubiquitin-mediated proteasomal degradation of proteins with mutations consistently associated with the development of clear cell renal cell carcinoma (ccRCC). Despite extensive investigations conducted worldwide, there is a notable lack of data concerning VHL mutations in sporadic ccRCC patients from India. Our study aimed to investigate the sporadic VHL mutations within the tumours of 210 ccRCC patients without a familial history of VHL disease. We extracted genomic DNA from tumour and adjacent normal tissues, PCR amplified and sequenced the VHL gene. In silico tools were used assess the damaging potential of missense variants on pVHL structure and stability. Protein-protein docking and protein flexibility molecular docking simulation study were employed to study the interaction between wild-type and mutated VHL models with Elongin C. Sequence analysis revealed seven novel missense mutations in patient tumour tissues p.(Val170Phe), p.(Arg69Cys), p.(Phe76Leu), p.(Glu173Asp), p.(Leu201Val), p.(His208Leu), p.(Arg205Pro). I-Mutant 2.0 indicated these mutations reduced pVHL stability (ΔΔG < -0.5 kcal/mol). Protein Flexibility-Molecular Dynamic (MD) Simulation study indicated that mutations weaken the interaction of VHL with Elongin C, with V170F showing the most significant reduction in binding quality and stability. In conclusion, this study introduces novel genetic data from an understudied population and highlights the impact of VHL mutations on its interaction with Elongin C. These findings contribute to our understanding of the molecular basis of VHL-related pathologies and may guide future therapeutic strategies targeting these interactions.https://doi.org/10.1038/s41598-025-95875-1VHLRenal cell carcinoma (RCC)Novel mutationsIn silicoProtein flexibility modelling |
| spellingShingle | Srilagna Chatterjee Nirvika Paul Anwesha Das Sarbashri Bank Biswabandhu Bankura Ravi Prakash Yadav Kunal Sarkar Soumen Saha Subhajit Malakar Sunirmal Choudhury Sudakshina Ghosh Madhusudan Das Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India Scientific Reports VHL Renal cell carcinoma (RCC) Novel mutations In silico Protein flexibility modelling |
| title | Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India |
| title_full | Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India |
| title_fullStr | Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India |
| title_full_unstemmed | Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India |
| title_short | Molecular dynamics reveal potential effects of novel VHL variants on VHL-Elongin C binding in ccRCC patients from Eastern India |
| title_sort | molecular dynamics reveal potential effects of novel vhl variants on vhl elongin c binding in ccrcc patients from eastern india |
| topic | VHL Renal cell carcinoma (RCC) Novel mutations In silico Protein flexibility modelling |
| url | https://doi.org/10.1038/s41598-025-95875-1 |
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