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N-domain of angiotensin-converting enzyme hydrolyzes human and rat amyloid-?(1-16) peptides as arginine specific endopeptidase potentially enhancing risk of Alzheimer's disease.


ABSTRACT: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Amyloid-? (A?) aggregation is likely to be the major cause of AD. In contrast to humans and other mammals, that share the same A? sequence, rats and mice are invulnerable to AD-like neurodegenerative pathologies, and A? of these rodents (ratA?) has three amino acid substitutions in the metal-binding domain 1-16 (MBD). Angiotensin-converting enzyme (ACE) cleaves A?-derived peptide substrates, however, there are contradictions concerning the localization of the cleavage sites within A? and the roles of each of the two ACE catalytically active domains in the hydrolysis. In the current study by using mass spectrometry and molecular modelling we have tested a set of peptides corresponding to MBDs of A? and ratA? to get insights on the interactions between ACE and these A? species. It has been shown that the N-domain of ACE (N-ACE) acts as an arginine specific endopeptidase on the A? and ratA? MBDs with C-amidated termini, thus assuming that full-length A? and ratA? can be hydrolyzed by N-ACE in the same endopeptidase mode. Taken together with the recent data on the molecular mechanism of zinc-dependent oligomerization of A?, our results suggest a modulating role of N-ACE in AD pathogenesis.

SUBMITTER: Kugaevskaya EV 

PROVIDER: S-EPMC5762728 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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N-domain of angiotensin-converting enzyme hydrolyzes human and rat amyloid-β(1-16) peptides as arginine specific endopeptidase potentially enhancing risk of Alzheimer's disease.

Kugaevskaya Elena V EV   Veselovsky Alexander V AV   Indeykina Maria I MI   Solovyeva Nina I NI   Zharkova Maria S MS   Popov Igor A IA   Nikolaev Eugene N EN   Mantsyzov Alexey B AB   Makarov Alexander A AA   Kozin Sergey A SA  

Scientific reports 20180110 1


Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Amyloid-β (Aβ) aggregation is likely to be the major cause of AD. In contrast to humans and other mammals, that share the same Aβ sequence, rats and mice are invulnerable to AD-like neurodegenerative pathologies, and Aβ of these rodents (ratAβ) has three amino acid substitutions in the metal-binding domain 1-16 (MBD). Angiotensin-converting enzyme (ACE) cleaves Aβ-derived peptide substrates, however, there are contradiction  ...[more]

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