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 1083-351XFull text not available from this repository.
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.
|Journal or Publication Title:||Journal of Biological Chemistry|
|Subjects:||Q Science > QH Natural history > QH301 Biology|
|Departments:||Faculty of Health and Medicine > Biomedical & Life Sciences|
|Deposited By:||Dr Edward Parkin|
|Deposited On:||11 Jun 2008 10:30|
|Last Modified:||24 Jun 2016 01:31|
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