Journal
CHEMBIOCHEM
Volume 17, Issue 18, Pages 1732-1737Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201600255
Keywords
amyloid beta-peptides; copper; fluorescence spectroscopy; kinetics; reaction mechanism
Funding
- Engineering and Physical Sciences Research Council (EPSRC)
- Biotechnology and Biosciences Research Council (BBSRC) of the UK
- Engineering and Physical Sciences Research Council [1375470] Funding Source: researchfish
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Mutations and post-translational modifications of amyloid- (A) peptide in its Nterminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two A peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with A peptide phosphorylated at serine8 (pS8). All three peptides bind to copper with a similar rate as the wild-type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50% faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper-bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of A beta.
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