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Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2).
J Transl Med. 2020 08 24; 18(1):321.JT

Abstract

BACKGROUND

The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2.

METHODS

We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program.

RESULTS

Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian.

CONCLUSIONS

We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.

Links

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Authors+Show Affiliations

Guo X
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vumc.org. Department of Biomedical Informatics and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. xingyi.guo@vumc.org.
Chen Z
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. Department of Biomedical Informatics and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA.
Xia Y
Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, China.
Lin W
The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China. wlin@zju.edu.cn.
Li H
Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, 91008, USA. holi@coh.org.

MeSH

Amino Acid SubstitutionAngiotensin-Converting Enzyme 2BetacoronavirusBinding SitesCOVID-19Coronavirus InfectionsDNA Mutational AnalysisDatabases, GeneticGenetic Predisposition to DiseaseGenetic VariationGeographyHumansModels, MolecularMolecular Docking SimulationMutation, MissensePandemicsPeptidyl-Dipeptidase APneumonia, ViralPolymorphism, Single NucleotideProtein BindingProtein Interaction Domains and MotifsProtein Structure, SecondarySARS-CoV-2Spike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

32831104

Citation

Guo, Xingyi, et al. "Investigation of the Genetic Variation in ACE2 On the Structural Recognition By the Novel Coronavirus (SARS-CoV-2)." Journal of Translational Medicine, vol. 18, no. 1, 2020, p. 321.
Guo X, Chen Z, Xia Y, et al. Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2). J Transl Med. 2020;18(1):321.
Guo, X., Chen, Z., Xia, Y., Lin, W., & Li, H. (2020). Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2). Journal of Translational Medicine, 18(1), 321. https://doi.org/10.1186/s12967-020-02486-7
Guo X, et al. Investigation of the Genetic Variation in ACE2 On the Structural Recognition By the Novel Coronavirus (SARS-CoV-2). J Transl Med. 2020 08 24;18(1):321. PubMed PMID: 32831104.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2). AU - Guo,Xingyi, AU - Chen,Zhishan, AU - Xia,Yumin, AU - Lin,Weiqiang, AU - Li,Hongzhi, Y1 - 2020/08/24/ PY - 2020/05/15/received PY - 2020/08/13/accepted PY - 2020/8/25/entrez PY - 2020/8/25/pubmed PY - 2020/9/15/medline KW - ACE2 KW - COVID-19 KW - Missense KW - S-protein KW - SARS-CoV-2 SP - 321 EP - 321 JF - Journal of translational medicine JO - J Transl Med VL - 18 IS - 1 N2 - BACKGROUND: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. METHODS: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program. RESULTS: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian. CONCLUSIONS: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment. SN - 1479-5876 UR - https://www.unboundmedicine.com/medline/citation/32831104/Investigation_of_the_genetic_variation_in_ACE2_on_the_structural_recognition_by_the_novel_coronavirus__SARS_CoV_2__ DB - PRIME DP - Unbound Medicine ER -