文章：

GPx7与GPx8的计算诱变研究：罕见遗传性与体细胞错义突变的结构稳定性解析及其在癌症发展中的意义

Computational Mutagenesis of GPx7 and GPx8: Structural and Stability Insights into Rare Genetic and Somatic Missense Mutations and Their Implications for Cancer Development

原文发布日期：31 December 2024

DOI: 10.3390/cancers17010105

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:Somatic and genetic mutations in glutathione peroxidases (GPxs), including GPx7 and GPx8, have been linked to intellectual disability, microcephaly, and various tumors. GPx7 and GPx8 evolved the latest among the GPx enzymes and are present in the endoplasmic reticulum. Although lacking a glutathione binding domain, GPx7 and GPx8 possess peroxidase activity that helps the body respond to cellular stress. However, the protein mutations in these peroxidases remain relatively understudied.Methods:By elucidating the structural and stability consequences of missense mutations, this study aims to provide insights into the pathogenic mechanisms involved in different cancers, thereby aiding clinical diagnosis, treatment strategies, and the development of targeted therapies. We performed saturated computational mutagenesis to analyze 2926 and 3971 missense mutations of GPx7 and GPx8, respectively. Results: The results indicate that G153H and G153F in GPx7 are highly destabilizing, while E93M and W142F are stabilizing. In GPx8, N74W and G173W caused the most instability while S70I and S119P increased stability. Our analysis shows that highly destabilizing somatic and genetic mutations are more likely pathogenic compared to stabilizing mutations. Conclusions: This comprehensive analysis of missense mutations in GPx7 and GPx8 provides critical insights into their impact on protein structure and stability, contributing to a deeper understanding of the roles of somatic mutations in cancer development and progression. These findings can inform more precise clinical diagnostics and targeted treatment approaches for cancers.

摘要翻译： 

背景/目的：谷胱甘肽过氧化物酶（GPxs）中的体细胞与遗传突变，包括GPx7和GPx8，已被证实与智力障碍、小头畸形及多种肿瘤相关。GPx7和GPx8是GPx酶系中进化最晚的成员，定位于内质网。尽管缺乏谷胱甘肽结合结构域，GPx7和GPx8仍具有过氧化物酶活性，协助机体应对细胞应激。然而，这些过氧化物酶中的蛋白质突变研究仍相对不足。方法：通过阐明错义突变对蛋白质结构与稳定性的影响，本研究旨在揭示不同癌症的致病机制，从而为临床诊断、治疗策略及靶向疗法开发提供依据。我们采用饱和计算诱变技术，分别分析了GPx7的2926个和GPx8的3971个错义突变。结果：分析显示，GPx7中的G153H和G153F突变具有高度去稳定作用，而E93M和W142F则起稳定作用。在GPx8中，N74W和G173W导致最显著的不稳定性，而S70I和S119P则增强了稳定性。我们的研究表明，与稳定突变相比，高度去稳定的体细胞及遗传突变更可能具有致病性。结论：本研究对GPx7和GPx8错义突变的全面分析，为理解这些突变对蛋白质结构与稳定性的影响提供了关键见解，有助于深入认识体细胞突变在癌症发生与发展中的作用。这些发现可为癌症的精准临床诊断与靶向治疗策略提供参考。

原文链接：

Computational Mutagenesis of GPx7 and GPx8: Structural and Stability Insights into Rare Genetic and Somatic Missense Mutations and Their Implications for Cancer Development