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

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dc.contributor.authorDanilov, Sergei Men_ZA
dc.contributor.authorGordon, Kerryen_ZA
dc.contributor.authorNesterovitch, Andrew Ben_ZA
dc.contributor.authorLünsdorf, Heinrichen_ZA
dc.contributor.authorChen, Zhenlongen_ZA
dc.contributor.authorCastellon, Maricelaen_ZA
dc.contributor.authorPopova, Isolda Aen_ZA
dc.contributor.authorKalinin, Sergeyen_ZA
dc.contributor.authorMendonca, Emmaen_ZA
dc.contributor.authorPetukhov, Pavel Aen_ZA
dc.date.accessioned2016-01-11T06:55:12Z
dc.date.available2016-01-11T06:55:12Z
dc.date.issued2011en_ZA
dc.description.abstractBACKGROUND: 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.identifier.apacitationDanilov, S. M., Gordon, K., Nesterovitch, A. B., Lünsdorf, H., Chen, Z., Castellon, M., ... Petukhov, P. A. (2011). An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding. <i>PLoS One</i>, http://hdl.handle.net/11427/16294en_ZA
dc.identifier.chicagocitationDanilov, Sergei M, Kerry Gordon, Andrew B Nesterovitch, Heinrich Lünsdorf, Zhenlong Chen, Maricela Castellon, Isolda A Popova, Sergey Kalinin, Emma Mendonca, and Pavel A Petukhov "An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding." <i>PLoS One</i> (2011) http://hdl.handle.net/11427/16294en_ZA
dc.identifier.citationDanilov, 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.0025952en_ZA
dc.identifier.ris TY - Journal Article AU - Danilov, Sergei M AU - Gordon, Kerry AU - Nesterovitch, Andrew B AU - Lünsdorf, Heinrich AU - Chen, Zhenlong AU - Castellon, Maricela AU - Popova, Isolda A AU - Kalinin, Sergey AU - Mendonca, Emma AU - Petukhov, Pavel A AB - 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). DA - 2011 DB - OpenUCT DO - 10.1371/journal.pone.0025952 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2011 T1 - An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding TI - An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding UR - http://hdl.handle.net/11427/16294 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16294
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0025952
dc.identifier.vancouvercitationDanilov SM, Gordon K, Nesterovitch AB, Lünsdorf H, Chen Z, Castellon M, et al. An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding. PLoS One. 2011; http://hdl.handle.net/11427/16294.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDivision of Medical Biochemistryen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis 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.holder© 2011 Danilov et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherMoltingen_ZA
dc.subject.otherCHO cellsen_ZA
dc.subject.otherBlooden_ZA
dc.subject.otherDimerizationen_ZA
dc.subject.otherSubstitution mutationen_ZA
dc.subject.otherBlood plasmaen_ZA
dc.subject.otherHEK 293 cellsen_ZA
dc.subject.otherHydrogen bondingen_ZA
dc.titleAn angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE sheddingen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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