Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics.
CATH database
COVID-19
Functional family
Human genetic variation
Immunity
Protein binding affinity prediction
Protein structure complex
SARS-CoV-2: human protein interaction
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 06 2024
20 06 2024
Historique:
received:
07
11
2023
accepted:
07
05
2024
medline:
21
6
2024
pubmed:
21
6
2024
entrez:
20
6
2024
Statut:
epublish
Résumé
The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19. In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and their human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed the impact of missense variants occurring in the protein-protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities for the human viral protein complexes. We predicted a total of 26 affinity-enhancing variants from 13 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed. Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.
Identifiants
pubmed: 38902252
doi: 10.1038/s41598-024-61541-1
pii: 10.1038/s41598-024-61541-1
doi:
Substances chimiques
Viral Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14208Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/W003368/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S020144/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M009513/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : 60175814
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/R014892/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 221327/Z/20/Z
Pays : United Kingdom
Organisme : Ministry of Higher Education, Malaysia
ID : FRGS/1/2020/STG01/UKM/02/3
Informations de copyright
© 2024. Crown.
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