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Investigation into the mechanism of homo- and heterodimerization of angiotensin-converting enzyme

DOI: 10.1124/mol.117.110866 DOI Help

Authors: J. Albert Abrie (Roche Sequencing Solutions) , Wessel J. A. Moolman (University of Cape Town) , Gyles E. Cozier (University of Bath) , Sylva L. Schwager (University of Cape Town) , K. Ravi Acharya (University of Bath) , Edward D. Sturrock (University of Cape Town)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Pharmacology

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 14863 , 12342

Open Access Open Access

Abstract: Angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system (RAS), which is primarily responsible for blood pressure homeostasis. Studies have shown that ACE inhibitors yield cardiovascular benefits that cannot be entirely attributed to the inhibition of ACE catalytic activity. It is possible that these benefits are due to interactions between ACE and RAS receptors that mediate the protective arm of the RAS, such as the angiotensin-II receptor type 2 (AT2R) and the receptor MAS. Therefore, in this study we investigated the molecular interactions of ACE, including ACE homodimerization and heterodimerization with AT2R and MAS respectively. Molecular interactions were assessed by fluorescence resonance energy transfer and bi-molecular fluorescence complementation in human embryonic kidney-293 cells and Chinese hamster ovary-K1 cells transfected with vectors encoding fluorophore-tagged proteins. The specificity of dimerization was verified by competition experiments using untagged proteins. These techniques were used to study several potential requirements for testis ACE (tACE) dimerization as well as the effect of ACE inhibitors on both somatic ACE (sACE) and tACE dimerization. We demonstrated constitutive homodimerization of somatic ACE and of both its domains separately, as well as heterodimerization of both sACE and tACE with AT2R, but not MAS. Additionally, we investigated both soluble sACE and sACE N-domain using size exclusion chromatography small-angle X-ray scattering and we observed dimers in solution for both forms of the enzyme. Our results suggest that ACE homo- and heterodimerization does occur under physiological conditions.

Journal Keywords: ACE inhibitors; Angiotensin converting enzyme (ACE); Angiotensin receptors

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B21-High Throughput SAXS

Added On: 30/01/2018 10:31


Discipline Tags:

Health & Wellbeing Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)