Bioinformatics analysis of missense mutations in CXCR1 implicates altered protein stability and function

Tumor discovery Pub Date : 2024-03-21 DOI:10.36922/td.2512
Shah Kamal, Amanullah Amanullah, Qingqing Wang, Najeeb Ullah, Gohar Mushtaq, Muhammad Nasir Iqbal, Mohammad Amjad Kamal
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Abstract

Human CXCR1 is a G-protein α subunit i (Gαi)-coupled receptor (GPCR) that plays an important role in promoting leukocyte recruitment and activation in inflammatory regions; thus, its genetic contribution to human disorders warrants further investigation. In this study, we investigated whether oncogenic missense mutations in CXCR1 would affect its activity and hinder its ability to interact with its ligand. This study utilized a bioinformatics approach and employed precise and thorough computational methods to gain insights into the molecular characteristics of mutated CXCR1 that are responsible for causing diseases. I-TASSER was used to construct a mutant model with the required mutations. Schrödinger’s Desmond software was used to evaluate how mutations affect the stability and function of proteins. In this study, 299 CXCR1 missense mutations were examined; 53 of these were reported to be disease-causing, five of which were directly associated with cancer. The impact of the three cancer-causing mutations (N57D, R135C, and P302S) on protein stability and function was subsequently examined through computational analysis. Positions N57, R135, and P302 were determined to be highly conserved, and substitutions with aspartic acid (D), cysteine (C), and serine (S), respectively, could impair CXCR1 activity. Hence, our findings suggested that these mutations could alter CXCR1 ligand binding activity, lowering the risk of cancer and helping patients defend against pathogen invasion during a neutrophil-mediated innate immune response.
对 CXCR1 错义突变的生物信息学分析显示蛋白质稳定性和功能发生了改变
人类 CXCR1 是一种 G 蛋白 α 亚基 i(Gαi)耦合受体(GPCR),在促进炎症区域白细胞募集和活化方面发挥着重要作用;因此,它对人类疾病的遗传贡献值得进一步研究。在本研究中,我们调查了 CXCR1 的致癌错义突变是否会影响其活性并阻碍其与配体相互作用的能力。本研究利用生物信息学方法,采用精确而全面的计算方法来深入了解导致疾病的突变 CXCR1 的分子特征。I-TASSER 被用来构建具有所需突变的突变体模型。Schrödinger's Desmond 软件用于评估突变如何影响蛋白质的稳定性和功能。在这项研究中,共检测了 299 个 CXCR1 错义突变;据报道,其中 53 个是致病突变,其中 5 个与癌症直接相关。随后,通过计算分析研究了三种致癌突变(N57D、R135C 和 P302S)对蛋白质稳定性和功能的影响。结果表明,N57、R135 和 P302 位置高度保守,分别与天冬氨酸 (D)、半胱氨酸 (C) 和丝氨酸 (S) 发生置换会损害 CXCR1 的活性。因此,我们的研究结果表明,这些突变可改变 CXCR1 配体的结合活性,从而降低癌症风险,并帮助患者在中性粒细胞介导的先天性免疫反应中抵御病原体的入侵。
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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