title: Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor.
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.
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706-1396, USA.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Middleton
authors.forename: Peter
authors.initials: P
authors.lastname: Marek
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.forename: Chi-cheng
authors.initials: CC
authors.lastname: Chiu
authors.forename: Sadanand
authors.initials: S
authors.lastname: Singh
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Woys
authors.forename: Juan J
authors.initials: JJ
authors.lastname: de Pablo
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Raleigh
authors.forename: Martin T
authors.initials: MT
authors.lastname: Zanni
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors*; D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D007700:Kinetics; D017433:Protein Structure, Secondary; D051381:Rats; D013055:Spectrophotometry, Infrared / Q000295:instrumentation / Q000379:methods*; D013997:Time Factors
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide