Comprehensive in silico characterization of nonsynonymous SNPs in the human ezrin (EZR) gene and their role in disease pathogenesis

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports Pub Date : 2025-03-08 DOI:10.1016/j.bbrep.2025.101972

Sadia Akter , Mohtasim Fuad , Zimam Mahmud, Sonia Tamanna, Mohammad Sayem, Khalid Hasan Raj, Md. Zakir Hossain Howlader

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Abstract

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.

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人ezrin （EZR）基因非同义snp的综合硅表征及其在疾病发病机制中的作用

Ezrin （EZR）是肌动蛋白骨架与质膜之间的重要连接物。它与参与癌症相关信号通路的蛋白质相互作用。为了评估非同义单核苷酸多态性（nssnp）对EZR结构和功能的影响，我们使用了生物信息学工具（SIFT、polyphen2、PROVEAN、PhD-SNP、snps&go、SuSPect和FATHMM）并鉴定了有害变异。使用MUpro、mCSM、I-Mutant 2.0和DynaMut2进行稳定性分析，发现6个不稳定的nssnp （F240S、H288D、I248T、L59Q、L125S和L225P）。使用HOPE、MutPred2、AlphaFold、Swiss-Model进行结构建模，使用HADDOCK 2.4进行蛋白对接，评估对EZR-EBP50复合物的影响。结合自由能计算、盐桥分析和界面残基定位进一步证实，L225P、F240S和I248T突变显著破坏了EZR-EBP50相互作用，可能破坏关键的信号通路。分子动力学模拟表明，突变型EZR蛋白表现出稳定性、柔韧性和氢键的降低。这是EZR首次全面的计算机分析，突出了可能导致疾病进展的致病性非单核苷酸多态性。这些发现为实验验证提供了基础，并可能为ezr相关病理的靶向治疗提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

4.60

自引率

0.00%

发文量

191

审稿时长

59 days

期刊介绍： Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.