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Beta SARS-CoV-2 Spike bound to mouse ACE2 (local)Beta SARS-CoV-2 Spike bound to mouse ACE2 (local)
Structural highlights
FunctionGCAM_MOUSE ACE2_MOUSE Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II. Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin. Also cleaves other biological peptides, such as apelins, casomorphins and dynorphin A (By similarity). By cleavage of angiotensin II, may be an important regulator of heart function (PubMed:12075344, PubMed:12967627). By cleavage of angiotensin II, may also have a protective role in acute lung injury (PubMed:16001071). Plays an important role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19, regulating its trafficking on the cell surface and its activity (PubMed:18424768, PubMed:19185582, PubMed:22677001).[UniProtKB:Q9BYF1][1] [2] [3] [4] [5] [6] Publication Abstract from PubMedInvestigation of potential hosts of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial to understanding future risks of spillover and spillback. SARS-CoV-2 has been reported to be transmitted from humans to various animals after requiring relatively few mutations. There is significant interest in describing how the virus interacts with mice as they are well adapted to human environments, are used widely as infection models and can be infected. Structural and binding data of the mouse ACE2 receptor with the Spike protein of newly identified SARS-CoV-2 variants are needed to better understand the impact of immune system evading mutations present in variants of concern (VOC). Previous studies have developed mouse-adapted variants and identified residues critical for binding to heterologous ACE2 receptors. Here we report the cryo-EM structures of mouse ACE2 bound to trimeric Spike ectodomains of four different VOC: Beta, Omicron BA.1, Omicron BA.2.12.1 and Omicron BA.4/5. These variants represent the oldest to the newest variants known to bind the mouse ACE2 receptor. Our high-resolution structural data complemented with bio-layer interferometry (BLI) binding assays reveal a requirement for a combination of mutations in the Spike protein that enable binding to the mouse ACE2 receptor. Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range.,Ni D, Turelli P, Beckert B, Nazarov S, Uchikawa E, Myasnikov A, Pojer F, Trono D, Stahlberg H, Lau K PLoS Pathog. 2023 Apr 5;19(4):e1011206. doi: 10.1371/journal.ppat.1011206. , eCollection 2023 Apr. PMID:37018380[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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