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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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1437-4315
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Volume 387, Issue 8

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Homologous substitution of ACE C-domain regions with N-domain sequences: effect on processing, shedding, and catalytic properties

Zenda L. Woodman
  • Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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/ Sylva L.U. Schwager
  • Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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/ Pierre Redelinghuys
  • Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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/ Anthony J. Chubb
  • Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa and Present address: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
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/ Elizabeth L. van der Merwe / Mario R.W. Ehlers / Edward D. Sturrock
  • Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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Published Online: 2006-08-09 | DOI: https://doi.org/10.1515/BC.2006.129

Abstract

Angiotensin-converting enzyme (ACE) exists as two isoforms: somatic ACE (sACE), comprised of two homologous N and C domains, and testis ACE (tACE), comprised of the C domain only. The N and C domains are both active, but show differences in substrate and inhibitor specificity. While both isoforms are shed from the cell surface via a sheddase-mediated cleavage, tACE is shed much more efficiently than sACE. To delineate the regions of tACE that are important in catalytic activity, intracellular processing, and regulated ectodomain shedding, regions of the tACE sequence were replaced with the corresponding N-domain sequence. The resultant chimeras C1–163Ndom-ACE, C417–579Ndom-ACE, and C583–623Ndom-ACE were processed to the cell surface of transfected Chinese hamster ovary (CHO) cells, and were cleaved at the identical site as that of tACE. They also showed acquisition of N-domain-like catalytic properties. Homology modelling of the chimeric proteins revealed structural changes in regions required for tACE-specific catalytic activity. In contrast, C164–416Ndom-ACE and C191–214Ndom-ACE demonstrated defective intracellular processing and were neither enzymatically active nor shed. Therefore, critical elements within region D164–V416 and more specifically I191–T214 are required for the processing, cell-surface targeting, and enzyme activity of tACE, and cannot be substituted for by the homologous N-domain sequence.

Keywords: cooperativity; domain selectivity; proteolytic cleavage; sheddase

About the article

Corresponding author


Received: February 3, 2006

Accepted: June 1, 2006

Published Online: 2006-08-09

Published in Print: 2006-08-01


Citation Information: Biological Chemistry, Volume 387, Issue 8, Pages 1043–1051, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2006.129.

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