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J. Biol. Chem., Vol. 276, Issue 8, 5525-5532, February 23, 2001

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Increased Shedding of Angiotensin-converting Enzyme by a Mutation Identified in the Stalk Region^*

Melanie Eyries^§, Annie Michaud^¶, Jaap Deinum, Monique Agrapart, Jacques Chomilier^**, Cornelis Kramers, and Florent Soubrier^§§

From the  Institut National de la Santé et de la Recherche Médicale Unit 525, Faculté de médecine Pitié-Salpétrière, 91 Boulevard de l'Hôpital, 75013 Paris, France; the ^¶ Unit 36-Collège de France, 3 rue d'Ulm, 75005 Paris, France; the  Department of Internal Medicine I, University of Rotterdam, dr Molewaterplein 40 3015 GD Rotterdam, The Netherlands; the ^** Université Paris 6 and 7, CNRS UMR 7590, 4 place Jussieu, 75252 Paris Cedex 05, France; and the  Department of Pharmacology and Toxicology and Department of Internal Medicine, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

Angiotensin-converting enzyme (ACE), an enzyme that plays a major role in vasoactive peptide metabolism, is a type 1 ectoprotein, which is released from the plasma membrane by a proteolytic cleavage occurring in the stalk sequence adjacent to the membrane anchor. In this study, we have discovered the molecular mechanism underlying the marked increase of plasma ACE levels observed in three unrelated individuals. We have identified a Pro¹¹⁹⁹  Leu mutation in the juxtamembrane stalk region. In vitro analysis revealed that the shedding of [Leu¹¹⁹⁹]ACE was enhanced compared with wild-type ACE. The solubilization process of [Leu¹¹⁹⁹]ACE was stimulated by phorbol esters and inhibited by compound 3, an inhibitor of ACE-secretase. The results of Western blot analysis were consistent with a cleavage at the major described site (Arg¹²⁰³Ser¹²⁰⁴). Two-dimensional structural analysis of ACE showed that the mutated residue was critical for the positioning of a specific loop containing the cleavage site. We therefore propose that a local conformational modification caused by the Pro¹¹⁹⁹  Leu mutation leads to more accessibility at the stalk region for ACE secretase and is responsible for the enhancement of the cleavage-secretion process. Our results show that different molecular mechanisms are responsible for the common genetic variation of plasma ACE and for its more rare familial elevation.

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