Copper transporters? glutathione reactivity of products of Cu-A beta digestion by Neprilysin
Author(s)
Stefaniak, Ewelina
Plonka, Dawid
Szczerba, Paulina
Wezynfeld, Nina E
Bal, Wojciech
Type
Journal Article
Abstract
Aβ4–42 is the major subspecies of Aβ peptides characterized by avid Cu(II) binding via the ATCUN/NTS motif. It is thought to be produced in vivo proteolytically by neprilysin, but in vitro experiments in the presence of Cu(II) ions indicated preferable formation of C-terminally truncated ATCUN/NTS species including CuIIAβ4–16, CuIIAβ4–9, and also CuIIAβ12–16, all with nearly femtomolar affinities at neutral pH. Such small complexes may serve as shuttles for copper clearance from extracellular brain spaces, on condition they could survive intracellular conditions upon crossing biological barriers. In order to ascertain such possibility, we studied the reactions of CuIIAβ4–16, CuIIAβ4–9, CuIIAβ12–16, and CuIIAβ1–16 with reduced glutathione (GSH) under aerobic and anaerobic conditions using absorption spectroscopy and mass spectrometry. We found CuIIAβ4–16 and CuIIAβ4–9 to be strongly resistant to reduction and concomitant formation of Cu(I)–GSH complexes, with reaction times ∼10 h, while CuIIAβ12–16 was reduced within minutes and CuIIAβ1–16 within seconds of incubation. Upon GSH exhaustion by molecular oxygen, the CuIIAβ complexes were reformed with no concomitant oxidative damage to peptides. These finding reinforce the concept of Aβ4–x peptides as physiological trafficking partners of brain copper.
Date Issued
2020-04-06
Date Acceptance
2020-03-01
Citation
Inorganic Chemistry: including bioinorganic chemistry, 2020, 59 (7), pp.4186-4190
ISSN
0020-1669
Publisher
American Chemical Society
Start Page
4186
End Page
4190
Journal / Book Title
Inorganic Chemistry: including bioinorganic chemistry
Volume
59
Issue
7
Copyright Statement
© 2020 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY)
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000526414400006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Physical Sciences
Chemistry, Inorganic & Nuclear
Chemistry
BLOOD-BRAIN-BARRIER
CU(II) BINDING
PEPTIDE
COMPLEXES
OXIDATION
AFFINITY
ACCUMULATION
CLEARANCE
PRECURSOR
PROTEINS
Publication Status
Published
Date Publish Online
2020-03-26