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Interacting cogs in the machinery of the renin angiotensin system

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Abstract

Somatic angiotensin converting enzyme (sACE) is well-known for its role in blood pressure regulation and consequently, ACE inhibitors are widely prescribed for the treatment of hypertension. More than 60 years after the discovery of sACE, however, the molecular details of its substrate hydrolysis and inhibition are still poorly understood. Isothermal titration calorimetry, molecular dynamics simulations and fine epitope mapping suggest that substrate or inhibitor binding triggers a hinging motion between the two subdomains of each domain. Ligand binding to one domain further induces a conformational change in sACE to negatively affect the second domain’s function and can also cause dimerization between sACE molecules. This has been linked to an increase in sACE expression via intracellular signalling. Inhibitor-induced dimerization could thus decrease the efficacy of hypertension treatment. At present, the only structural information available for sACE are crystal structures of the truncated domains in the closed conformation due to the presence of ligands. These structures do not provide any information regarding the open active site conformation prior to ligand binding, the relative orientation of the two domains in full-length sACE, or the dimerization interface. To guarantee effective therapeutic intervention, further research is required to investigate the hinging, negative cooperativity and dimerization of sACE. This review describes our current understanding of these interactions and proposes how recent advances in cryo-electron microscopy could enable structural elucidation of their mechanisms.

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Abbreviations

Aβ:

Amyloid beta

ACE:

Angiotensin-converting enzyme

ACE2:

Angiotensin-converting enzyme-2

AcSDKP:

N-Acetyl serine-aspartate-lysine-proline

AngI:

Angiotensin I

EM:

Electron microscopy

FRET:

Fluorescence resonance energy transfer

ITC:

Isothermal titration calorimetry

MD:

Molecular dynamics

sACE:

Somatic ACE

SAXS:

Small-angle X-ray scattering

tACE:

Testis ACE

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Funding

This work was supported by a UK Global Challenge Research Fund grant: START-Synchrotron Techniques for African Research and Technology (Science and Technology Facilities Council grant ref. ST/R002754/1) and the National Research Foundation of South Africa (Grant No. 111798).

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  1. Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa

    Lizelle Lubbe & Edward D Sturrock

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  1. Lizelle Lubbe
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  2. Edward D Sturrock
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Correspondence to Edward D Sturrock.

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Lizelle Lubbe declares that she has no conflict of interest. Edward D. Sturrock declares that he has no conflict of interest.

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Lubbe, L., Sturrock, E.D. Interacting cogs in the machinery of the renin angiotensin system. Biophys Rev 11, 583–589 (2019). https://doi.org/10.1007/s12551-019-00555-w

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