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

Autor: Elena V. Kugaevskaya, Sergey A. Kozin, Maria I. Indeykina, M. S. Zharkova, N. I. Solovyeva, Igor Popov, Alexey B. Mantsyzov, Alexander V. Veselovsky, Alexander A. Makarov, Eugene N. Nikolaev
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-017-18567-5
Popis: 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 contradictions concerning the localization of the cleavage sites within Aβ 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 Aβ and ratAβ to get insights on the interactions between ACE and these Aβ species. It has been shown that the N-domain of ACE (N-ACE) acts as an arginine specific endopeptidase on the Aβ and ratAβ MBDs with C-amidated termini, thus assuming that full-length Aβ and ratAβ 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 Aβ, our results suggest a modulating role of N-ACE in AD pathogenesis.
Databáze: OpenAIRE
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