A Point Mutation in the Juxtamembrane Stalk of Human Angiotensin I-converting Enzyme Invokes the Action of a Distinct Secretase.

Alfalah, Marwan and Parkin, Edward T. and Jacob, Ralf and Sturrock, Edward D. and Mentele, Reinhard and Turner, Anthony J. and Hooper, Nigel M. and Naim, Hassan Y. (2001) A Point Mutation in the Juxtamembrane Stalk of Human Angiotensin I-converting Enzyme Invokes the Action of a Distinct Secretase. Journal of Biological Chemistry, 276 (24). pp. 21105-21109. ISSN 1083-351X

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Abstract

Angiotensin I-converting enzyme (ACE) is one of a number of integral membrane proteins that is proteolytically shed from the cell surface by a zinc metallosecretase. Mutagenesis of Asn631 to Gln in the juxtamembrane stalk region of ACE resulted in more efficient secretion of the mutant protein (ACENQ) as determined by pulse-chase analysis. In contrast to the wild-type ACE, the cleavage of ACENQ was not blocked by the metallosecretase inhibitor batimastat but by the serine protease inhibitor, 1,3-dichloroisocoumarin. Incubation of the cells at 15 °C revealed that ACENQ was cleaved in the endoplasmic reticulum, and mass spectrometric analysis of the secreted form of the protein indicated that it had been cleaved at the Asn635-Ser636 bond, three residues N-terminal to the normal secretase cleavage site at Arg638-Ser639. These data clearly show that a point mutation in the juxtamembrane region of an integral membrane protein can invoke the action of a mechanistically and spatially distinct secretase. In light of this observation, previous data on the effect of mutations in the juxtamembrane stalk of shed proteins being accommodated by a single secretase having a relaxed specificity need to be re-evaluated.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Biological Chemistry
Uncontrolled Keywords:
/dk/atira/pure/researchoutput/libraryofcongress/qh301
Subjects:
?? BIOCHEMISTRYCELL BIOLOGYMOLECULAR BIOLOGYQH301 BIOLOGY ??
ID Code:
9454
Deposited By:
Deposited On:
11 Jun 2008 09:30
Refereed?:
Yes
Published?:
Published
Last Modified:
14 Sep 2023 23:53