Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

Download Full-text

ACE2 the Janus-faced protein – from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19

Clinical Science ◽

10.1042/cs20200363 ◽

2020 ◽

Vol 134 (7) ◽

pp. 747-750 ◽

Cited By ~ 20

Author(s):

Rhian M. Touyz ◽

Hongliang Li ◽

Christian Delles

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Basic Science ◽

Physiological Role ◽

Ang Ii ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Multifunctional Protein ◽

Angiotensin Converting Enzyme 2

Abstract Angiotensin converting enzyme 2 (ACE2) is the major enzyme responsible for conversion of Ang II into Ang-(1-7). It also acts as the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, which causes Coronavirus Disease (COVID)-19. In recognition of the importance of ACE2 and to celebrate 20 years since its discovery, the journal will publish a focused issue on the basic science and (patho)physiological role of this multifunctional protein.

Download Full-text

Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2

10.1101/2020.06.29.178459 ◽

2020 ◽

Cited By ~ 8

Author(s):

Huihui Mou ◽

Brian D. Quinlan ◽

Haiyong Peng ◽

Yan Guo ◽

Shoujiao Peng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Viral Receptor ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Binding Domains ◽

Protein Receptor ◽

Horseshoe Bat ◽

Horseshoe Bats

SUMMARYThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat (R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

Download Full-text

Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features

Molecules ◽

10.3390/molecules25245906 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5906

Author(s):

Sk. Sarif Hassan ◽

Shinjini Ghosh ◽

Diksha Attrish ◽

Pabitra Pal Choudhury ◽

Alaa A. A. Aljabali ◽

...

Keyword(s):

Amino Acids ◽

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Comprehensive Analysis ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Protein Receptor

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22–42, aa 79–84, and aa 330–393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

Download Full-text

Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection

10.1101/2020.02.24.963348 ◽

2020 ◽

Cited By ~ 16

Author(s):

Pei-Hui Wang ◽

Yun Cheng

Keyword(s):

Angiotensin Converting Enzyme ◽

Emerging Infectious Diseases ◽

Cell Receptor ◽

Host Cells ◽

Cellular Receptor ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Host Cell Receptor ◽

Coronavirus Infection ◽

Entry Receptor

AbstractThe ongoing outbreak of a new coronavirus (2019-nCoV) causes an epidemic of acute respiratory syndrome in humans. 2019-nCoV rapidly spread to national regions and multiple other countries, thus, pose a serious threat to public health. Recent studies show that spike (S) proteins of 2019-nCoV and SARS-CoV may use the same host cell receptor called angiotensin-converting enzyme 2 (ACE2) for entering into host cells. The affinity between ACE2 and 2019-nCoV S is much higher than ACE2 binding to SARS-CoV S protein, explaining that why 2019-nCoV seems to be more readily transmitted from the human to human. Here, we reported that ACE2 can be significantly upregulated after infection of various viruses including SARS-CoV and MERS-CoV. Basing on findings here, we propose that coronavirus infection can positively induce its cellular entry receptor to accelerate their replication and spread, thus drugs targeting ACE2 expression may be prepared for the future emerging infectious diseases caused by this cluster of viruses.

Download Full-text

Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

Biomedicines ◽

10.3390/biomedicines9081038 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1038

Author(s):

Deborah Giordano ◽

Luigi De Masi ◽

Maria Antonia Argenio ◽

Angelo Facchiano

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico Analysis ◽

Host Cells ◽

Spike Protein ◽

Cellular Receptor ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

The World ◽

Silico Analysis

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

Download Full-text

Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.732690 ◽

2021 ◽

Vol 12 ◽

Author(s):

Keiji Kuba ◽

Tomokazu Yamaguchi ◽

Josef M. Penninger

Keyword(s):

Angiotensin Converting Enzyme ◽

Neutralizing Antibodies ◽

Cell Entry ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Angiotensin Converting Enzyme 2 ◽

Infected People ◽

Critical Attention ◽

Novel Coronavirus

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

Download Full-text