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Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor.

Authors :
Middleton CT
Marek P
Cao P
Chiu CC
Singh S
Woys AM
de Pablo JJ
Raleigh DP
Zanni MT
Source :
Nature chemistry [Nat Chem] 2012 Mar 11; Vol. 4 (5), pp. 355-60. Date of Electronic Publication: 2012 Mar 11.
Publication Year :
2012

Abstract

Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal β-sheet instead. At 24 h after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.

Details

Language :
English
ISSN :
1755-4349
Volume :
4
Issue :
5
Database :
MEDLINE
Journal :
Nature chemistry
Publication Type :
Academic Journal
Accession number :
22522254
Full Text :
https://doi.org/10.1038/nchem.1293