Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis
Ezrin (EZR) is a crucial linker between the actin cytoskeleton and the plasma membrane. It interacts with proteins involved in cancer-related signaling pathways. To assess the impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on EZR structure and function, we employed bioinformatics t...
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Elsevier
2025-06-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580825000597 |
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| author | Sadia Akter Mohtasim Fuad Zimam Mahmud Sonia Tamanna Mohammad Sayem Khalid Hasan Raj Md. Zakir Hossain Howlader |
| author_facet | Sadia Akter Mohtasim Fuad Zimam Mahmud Sonia Tamanna Mohammad Sayem Khalid Hasan Raj Md. Zakir Hossain Howlader |
| author_sort | Sadia Akter |
| collection | DOAJ |
| description | Ezrin (EZR) is a crucial linker between the actin cytoskeleton and the plasma membrane. It interacts with proteins involved in cancer-related signaling pathways. To assess the impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on EZR structure and function, we employed bioinformatics tools (SIFT, PolyPhen-2, PROVEAN, PhD-SNP, SNPs&GO, SuSPect, and FATHMM) and identified deleterious variants. Stability analyses using MUpro, mCSM, I-Mutant 2.0, and DynaMut2 revealed six destabilizing nsSNPs (F240S, H288D, I248T, L59Q, L125S, and L225P). Structural modeling using HOPE, MutPred2, AlphaFold, Swiss-Model, and protein-protein docking using HADDOCK 2.4 assessed the impact on the EZR-EBP50 complex. Binding free energy calculations, salt bridge analysis, and interface residue mapping further confirmed that the L225P, F240S, and I248T mutations significantly impaired EZR-EBP50 interaction, potentially disrupting key signaling pathways. Molecular dynamics simulations indicated that mutant EZR proteins exhibited reduced stability, flexibility, and hydrogen bonding. This first comprehensive in silico analysis of EZR highlights pathogenic nsSNPs that may contribute to disease progression. These findings provide a foundation for experimental validation and may inform targeted therapies for EZR-related pathologies. |
| format | Article |
| id | doaj-art-1ae4bd221ae54ceaa631b0a77d5c22d9 |
| institution | OA Journals |
| issn | 2405-5808 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | Biochemistry and Biophysics Reports |
| spelling | doaj-art-1ae4bd221ae54ceaa631b0a77d5c22d92025-08-20T02:37:38ZengElsevierBiochemistry and Biophysics Reports2405-58082025-06-014210197210.1016/j.bbrep.2025.101972Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesisSadia Akter0Mohtasim Fuad1Zimam Mahmud2Sonia Tamanna3Mohammad Sayem4Khalid Hasan Raj5Md. Zakir Hossain Howlader6Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshDepartment of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshCorresponding author.; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshDepartment of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshDepartment of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshDepartment of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshDepartment of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, BangladeshEzrin (EZR) is a crucial linker between the actin cytoskeleton and the plasma membrane. It interacts with proteins involved in cancer-related signaling pathways. To assess the impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on EZR structure and function, we employed bioinformatics tools (SIFT, PolyPhen-2, PROVEAN, PhD-SNP, SNPs&GO, SuSPect, and FATHMM) and identified deleterious variants. Stability analyses using MUpro, mCSM, I-Mutant 2.0, and DynaMut2 revealed six destabilizing nsSNPs (F240S, H288D, I248T, L59Q, L125S, and L225P). Structural modeling using HOPE, MutPred2, AlphaFold, Swiss-Model, and protein-protein docking using HADDOCK 2.4 assessed the impact on the EZR-EBP50 complex. Binding free energy calculations, salt bridge analysis, and interface residue mapping further confirmed that the L225P, F240S, and I248T mutations significantly impaired EZR-EBP50 interaction, potentially disrupting key signaling pathways. Molecular dynamics simulations indicated that mutant EZR proteins exhibited reduced stability, flexibility, and hydrogen bonding. This first comprehensive in silico analysis of EZR highlights pathogenic nsSNPs that may contribute to disease progression. These findings provide a foundation for experimental validation and may inform targeted therapies for EZR-related pathologies.http://www.sciencedirect.com/science/article/pii/S2405580825000597EZR geneNonsynonymous mutationsFERM domainERM binding protein 50Ezrin binding domainMolecular docking |
| spellingShingle | Sadia Akter Mohtasim Fuad Zimam Mahmud Sonia Tamanna Mohammad Sayem Khalid Hasan Raj Md. Zakir Hossain Howlader Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis Biochemistry and Biophysics Reports EZR gene Nonsynonymous mutations FERM domain ERM binding protein 50 Ezrin binding domain Molecular docking |
| title | Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis |
| title_full | Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis |
| title_fullStr | Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis |
| title_full_unstemmed | Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis |
| title_short | Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis |
| title_sort | comprehensive in silico characterization of nonsynonymous snps in the human ezrin ezr gene and their role in disease pathogenesis |
| topic | EZR gene Nonsynonymous mutations FERM domain ERM binding protein 50 Ezrin binding domain Molecular docking |
| url | http://www.sciencedirect.com/science/article/pii/S2405580825000597 |
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