5amc
From Proteopedia
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/ACE_HUMAN ACE_HUMAN]] Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. | [[http://www.uniprot.org/uniprot/ACE_HUMAN ACE_HUMAN]] Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Angiotensin-1 converting enzyme (ACE), a zinc metallopeptidase, consists of two homologous catalytic domains (N and C) with different substrate specificities. Here we report kinetic parameters of five different forms of human ACE with various amyloid beta (Abeta) substrates together with high resolution crystal structures of N-domain in complex with Abeta fragments. For the physiological Abeta(1-16) peptide, a novel ACE cleavage site was found at His14/Gln15. Furthermore, Abeta(1-16) was preferentially cleaved by the individual N-domain; however, the presence of an inactive C-domain in full-length sACE greatly reduced enzyme activity and affected apparent selectivity. Two fluorogenic substrates, Abeta(4-10)Q and Abeta(4-10)Y underwent endoproteolytic cleavage at the Asp7/Ser8 bond with all ACE constructs showing greater catalytic efficiency for Abeta(4-10)Y. Surprisingly, in contrast to Abeta(1-16) and Abeta(4-10)Q, sACE showed positive domain cooperativity and the double C-domain (CC-sACE) construct no cooperativity towards Abeta(4-10)Y. The structures of the Abeta peptide-ACE complexes revealed a common mode of peptide binding for both domains which principally targets the C-terminal P2' position to the S2' pocket and recognises the main chain of the P1' peptide. It is likely that N-domain selectivity for the amyloid peptide is conferred through the N-domain specific S2' residue Thr358. Additionally, the N-domain can accommodate larger substrates through movement of the N-terminal helices, as suggested by the disorder of the hinge region in the crystal structures. Our findings are important for the design of domain selective inhibitors as the differences in domain-selectivity are more pronounced with the truncated domains compared to the more physiological full-length forms. This article is protected by copyright. All rights reserved. | ||
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| + | Kinetic and structural characterisation of amyloid-beta peptides hydrolysis by human angiotensin-1-converting enzyme.,Larmuth KM, Masuyer G, Douglas RG, Schwager SL, Acharya KR, Sturrock ED FEBS J. 2016 Jan 8. doi: 10.1111/febs.13647. PMID:26748546<ref>PMID:26748546</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5amc" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 09:00, 20 January 2016
Crystal structure of the Angiotensin-1 converting enzyme N-domain in complex with amyloid-beta fluorogenic fragment 4-10
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