Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-18567-5
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Funding
- Russian Science Foundation [14-24-00100, 14-14-00598]
- Russian Science Foundation [17-24-00004, 17-14-00052] Funding Source: Russian Science Foundation
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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Amyloid-beta (A beta) aggregation is likely to be the major cause of AD. In contrast to humans and other mammals, that share the same A beta sequence, rats and mice are invulnerable to AD-like neurodegenerative pathologies, and A beta of these rodents (ratA beta) has three amino acid substitutions in the metal-binding domain 1-16 (MBD). Angiotensin-converting enzyme (ACE) cleaves A beta-derived peptide substrates, however, there are contradictions concerning the localization of the cleavage sites within A beta 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 beta and ratA beta to get insights on the interactions between ACE and these A beta species. It has been shown that the N-domain of ACE (N-ACE) acts as an arginine specific endopeptidase on the A beta and ratA beta MBDs with C-amidated termini, thus assuming that full-length A beta and ratA beta 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 beta, our results suggest a modulating role of N-ACE in AD pathogenesis.
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