An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding

 

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dc.contributor.author Danilov, Sergei M en_ZA
dc.contributor.author Gordon, Kerry en_ZA
dc.contributor.author Nesterovitch, Andrew B en_ZA
dc.contributor.author Lünsdorf, Heinrich en_ZA
dc.contributor.author Chen, Zhenlong en_ZA
dc.contributor.author Castellon, Maricela en_ZA
dc.contributor.author Popova, Isolda A en_ZA
dc.contributor.author Kalinin, Sergey en_ZA
dc.contributor.author Mendonca, Emma en_ZA
dc.contributor.author Petukhov, Pavel A en_ZA
dc.date.accessioned 2016-01-11T06:55:12Z
dc.date.available 2016-01-11T06:55:12Z
dc.date.issued 2011 en_ZA
dc.identifier.citation Danilov, S. M., Gordon, K., Nesterovitch, A. B., Lünsdorf, H., Chen, Z., Castellon, M., ... & Schwartz, D. E. (2011). An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding. doi:10.1371/journal.pone.0025952 en_ZA
dc.identifier.uri http://hdl.handle.net/11427/16294
dc.identifier.uri http://dx.doi.org/10.1371/journal.pone.0025952
dc.description.abstract BACKGROUND: Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE. METHODOLOGY/PRINCIPAL FINDINGS: HEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE - between Arg1203 and Ser1204 - was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another. Conclusions/Significance The Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase). en_ZA
dc.language.iso eng en_ZA
dc.publisher Public Library of Science en_ZA
dc.rights This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_ZA
dc.rights.uri http://creativecommons.org/licenses/by/4.0 en_ZA
dc.source PLoS One en_ZA
dc.source.uri http://journals.plos.org/plosone en_ZA
dc.subject.other Molting en_ZA
dc.subject.other CHO cells en_ZA
dc.subject.other Blood en_ZA
dc.subject.other Dimerization en_ZA
dc.subject.other Substitution mutation en_ZA
dc.subject.other Blood plasma en_ZA
dc.subject.other HEK 293 cells en_ZA
dc.subject.other Hydrogen bonding en_ZA
dc.title An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding en_ZA
dc.type Journal Article en_ZA
dc.rights.holder © 2011 Danilov et al en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Medical Biochemistry en_ZA
uct.type.filetype Text
uct.type.filetype Image


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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.