Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2)
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Journal of Translational Medicine Open Access
RESEARCH
Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS‑CoV‑2) Xingyi Guo1,2*, Zhishan Chen1,2, Yumin Xia3, Weiqiang Lin4* and Hongzhi Li5*
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. Keywords: COVID-19, ACE2, SARS-CoV-2, S-protein, Missense
*Correspondence: [email protected]; [email protected]; [email protected] 1 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA 4 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China 5 Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91008, USA Full list of author information is available at the end of the article
Background The outbreak of the coronavirus disease 2019 (COVID19), caused by a novel (new) coronavirus (SARS-CoV-2), has been characterized as a global pandemic [1–5]. COVID-19 is rapidly spreading across the world and affecting all populations. It has been documented that the S-protein of SARS-CoV-2 plays a key role in the recognition to the peptidase domain (PD) of the Angiotensin converting enzyme (ACE2) in humans [6, 7]. The thr
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