scholarly journals The ectodomain shedding of angiotensin-converting enzyme is independent of its localisation in lipid rafts

2003 ◽  
Vol 116 (15) ◽  
pp. 3079-3087 ◽  
Author(s):  
E. T. Parkin
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Lipid Rafts ◽  
Ectodomain Shedding ◽  
Converting Enzyme

Localization of an N-Domain Region of Angiotensin-Converting Enzyme Involved in the Regulation of Ectodomain Shedding Using Monoclonal Antibodies

2005 ◽  
Vol 4 (2) ◽  
pp. 258-267 ◽  
Author(s):  
Irina V. Balyasnikova ◽  
Zenda L. Woodman ◽  
Ronald F. Albrecht ◽  
Ramanathan Natesh ◽  
K. Ravi Acharya ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Angiotensin Converting Enzyme ◽  
Ectodomain Shedding ◽  
Converting Enzyme

scholarly journals The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein

2004 ◽  
Vol 271 (12) ◽  
pp. 2539-2547 ◽  
Author(s):  
Tobias M. J. Allinson ◽  
Edward T. Parkin ◽  
Thomas P. Condon ◽  
Sylva L. U. Schwager ◽  
Edward D. Sturrock ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Ectodomain Shedding ◽  
Converting Enzyme

Roles of the juxtamembrane and extracellular domains of angiotensin-converting enzyme in ectodomain shedding

2001 ◽  
Vol 358 (1) ◽  
pp. 185-192 ◽  
Author(s):  
Susan PANG ◽  
Anthony J. CHUBB ◽  
Sylva L. U. SCHWAGER ◽  
Mario R. W. EHLERS ◽  
Edward D. STURROCK ◽  
...  
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
Active Form ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Critical Determinant ◽  
Terminal Domain ◽  
Cytosolic Domains ◽  
Identical Manner ◽  
Substrate Proteins

Angiotensin-converting enzyme (ACE) is one of a growing number of integral membrane proteins that is shed from the cell surface through proteolytic cleavage by a secretase. To investigate the requirements for ectodomain shedding, we replaced the glycosylphosphatidylinositol addition sequence in membrane dipeptidase (MDP) - a membrane protein that is not shed - with the juxtamembrane stalk, transmembrane (TM) and cytosolic domains of ACE. The resulting construct, MDP–STMACE, was targeted to the cell surface in a glycosylated and enzymically active form, and was shed into the medium. The site of cleavage in MDP–STMACE was identified by MS as the Arg374-Ser375 bond, corresponding to the Arg1203-Ser1204 secretase cleavage site in somatic ACE. The release of MDP–STMACE and ACE from the cells was inhibited in an identical manner by batimastat and two other hydroxamic acid-based zinc metallosecretase inhibitors. In contrast, a construct lacking the juxtamembrane stalk, MDP–TMACE, although expressed at the cell surface in an enzymically active form, was not shed, implying that the juxtamembrane stalk is the critical determinant of shedding. However, an additional construct, ACEΔC, in which the N-terminal domain of somatic ACE was fused to the stalk, TM and cytosolic domains, was also not shed, despite the presence of a cleavable stalk, implying that in contrast with the C-terminal domain, the N-terminal domain lacks a signal required for shedding. These data are discussed in the context of two classes of secretases that differ in their requirements for recognition of substrate proteins.

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 The N domain of somatic angiotensin-converting enzyme negatively regulates ectodomain shedding and catalytic activity

2005 ◽  
Vol 389 (3) ◽  
pp. 739-744 ◽  
Author(s):  
Zenda L. Woodman ◽  
Sylva L. U. Schwager ◽  
Pierre Redelinghuys ◽  
Adriana K. Carmona ◽  
Mario R. W. Ehlers ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Angiotensin Converting Enzyme ◽  
Catalytic Properties ◽  
Close Contact ◽  
Catalytic Efficiency ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Peptide Substrates ◽  
Recognition Motif ◽  
Hydrolysis Of

sACE (somatic angiotensin-converting enzyme) consists of two homologous, N and C domains, whereas the testis isoenzyme [tACE (testis ACE)] consists of a single C domain. Both isoenzymes are shed from the cell surface by a sheddase activity, although sACE is shed much less efficiently than tACE. We hypothesize that the N domain of sACE plays a regulatory role, by occluding a recognition motif on the C domain required for ectodomain shedding and by influencing the catalytic efficiency. To test this, we constructed two mutants: CNdom-ACE and CCdom-ACE. CNdom-ACE was shed less efficiently than sACE, whereas CCdom-ACE was shed as efficiently as tACE. Notably, cleavage occurred both within the stalk and the interdomain bridge in both mutants, suggesting that a sheddase recognition motif resides within the C domain and is capable of directly cleaving at both positions. Analysis of the catalytic properties of the mutants and comparison with sACE and tACE revealed that the kcat for sACE and CNdom-ACE was less than or equal to the sum of the kcat values for tACE and the N-domain, suggesting negative co-operativity, whereas the kcat value for the CCdom-ACE suggested positive co-operativity between the two domains. Taken together, the results provide support for (i) the existence of a sheddase recognition motif in the C domain and (ii) molecular flexibility of the N and C domains in sACE, resulting in occlusion of the C-domain recognition motif by the N domain as well as close contact of the two domains during hydrolysis of peptide substrates.

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.

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