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ORIGINAL RESEARCH ARTICLE

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

Shah Kamal1†* ,  Amanullah Amanullah1† ,  Qingqing Wang1 ,  Najeeb Ullah1 ,  Gohar Mushtaq2* ,  Muhammad Nasir Iqbal3 ,  Mohammad Amjad Kamal4,5,6,7,8
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1 Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China
2 Department of Biochemistry, Center for Scientific Research, Faculty of Medicine University, Idlib University, Idlib, Syria
3 Department of Bioinformatics, Faculty of Biological and Chemical Sciences, The lslamia Universityof Bahawalpur, Pakistan
4 Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and institutes for Systems Genetics, West China School of Nursing, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital. Sichuan University. 610212, Chengdu, China
5 King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
6 Department of Pharmacy, Faculty of Health and Life Sciences, Daffodil International University, Birulia, Savar, Dhaka -1216, Bangladesh
7 Centre for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
8 Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, Australia
Tumor Discovery 2024, 3(1), 2512 https://doi.org/10.36922/td.2512
Submitted: 22 December 2023 | Accepted: 21 February 2024 | Published: 21 March 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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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.

Keywords
CXCR1
Molecular dynamic simulation
Molecular modelling
G protein-coupled receptors
Funding
This work was supported by the National Natural Science Foundation of China (32270438, 32170498, 31970388), National Key Research and Development Program of China (2021YFF0702000, 2018YFD0900602), 1.3.5 Project for Disciplines of Excellence by the West China Hospital, Sichuan University (ZYJC21050), Science and Technology Department of Sichuan Province (2022YFH0116), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2023JC003).
Conflict of interest
The authors declare no conflict of interest.
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