Angiotensin-Converting Enzyme 2 Ectodomain Shedding Cleavage-Site Identification: Determinants and Constraints

Biochemistry ◽  
2011 ◽  
Vol 50 (23) ◽  
pp. 5182-5194 ◽  
Author(s):  
Zon W. Lai ◽  
Iresha Hanchapola ◽  
David L. Steer ◽  
A. Ian Smith
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Cleavage Site ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Site Identification

scholarly journals Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex

2020 ◽  
Author(s):  
Alberto Bartolomé ◽  
Jiani Liang ◽  
Pengfei Wang ◽  
David D. Ho ◽  
Utpal B. Pajvani
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Structural Similarity ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Membrane Bound ◽  
Novel Target ◽  
Functional Receptor

AbstractAngiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.

scholarly journals Characterization of Angiotensin-Converting Enzyme 2 Ectodomain Shedding from Mouse Proximal Tubular Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e85958 ◽  
Author(s):  
Fengxia Xiao ◽  
Joseph Zimpelmann ◽  
Samih Agaybi ◽  
Susan B. Gurley ◽  
Lawrence Puente ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Proximal Tubular Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Tubular Cells ◽  
Proximal Tubular

scholarly journals Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alberto Bartolomé ◽  
Jiani Liang ◽  
Pengfei Wang ◽  
David D. Ho ◽  
Utpal B. Pajvani
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Structural Similarity ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Membrane Bound ◽  
Novel Target ◽  
Functional Receptor

AbstractAngiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.

scholarly journals Oral epithelial expression of angiotensin converting enzyme-2: Implications for COVID-19 diagnosis and prognosis

2020 ◽  
Author(s):  
Mythily Srinivasan ◽  
Susan L Zunt ◽  
Lawrence I Goldblatt
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Clinical Symptoms ◽  
Cell Entry ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Immunofluorescence Analysis ◽  
Angiotensin Converting Enzyme 2 ◽  
Diagnosis And Prognosis ◽  
Oral Epithelial

AbstractThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses the angiotensin converting enzyme (ACE)-2 as the host receptor for target cell entry. The extent and distribution of ACE-2 has been associated with the clinical symptoms of coronavirus disease (COVID)-19. Here we show by immunofluorescence analysis that the ACE2 is abundantly expressed in oral mucosa, particularly in the surface epithelial cells suggesting that these cells could represent sites of entry for SARS-CoV-2. Further, together with the reports on ACE2 ectodomain shedding, we discuss the rationale for the hypothesis that the ACE-2 measurement in saliva could be a marker for COVID-19 infection during early phase following SARS-CoV-2 exposure.

scholarly journals Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
Xuesen Zhao ◽  
Danying Chen ◽  
Robert Szabla ◽  
Mei Zheng ◽  
Guoli Li ◽  
...  
Keyword(s):  
Animal Models ◽  
Angiotensin Converting Enzyme ◽  
Cleavage Site ◽  
Interspecies Transmission ◽  
Converting Enzyme ◽  
Wild Type ◽  
Furin Cleavage ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Furin Cleavage Site

ABSTRACT The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models. IMPORTANCE SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

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