The route from the folded to the amyloid state: exploring the potential energy surface of a drug-like miniprotein

Taricska, Nóra and Horváth, Dániel and K. Menyhárd, Dóra and Ákontz-Kiss, Hanna and Noji, Masahiro and Perczel, András (2019) The route from the folded to the amyloid state: exploring the potential energy surface of a drug-like miniprotein. CHEMISTRY-A EUROPEAN JOURNAL. pp. 1-27. ISSN 0947-6539 (print); 1521-3765 (online) (In Press)

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The amyloid formation of the folded segment of a variant of Exenatide (a marketed drug for Type-2 Diabetes Mellitus ) was studied by ECD and NMR. We found that the optimum temperature for E5 protein amyloidosis coincides with body temperature and requires well below physiological salt concentration. Decomposition of the ECD spectra and its barycentric representation on the folded-unfolded-amyloid potential energy surface allowed us to monitor the full range of molecular transformation of amyloidogenesis. We identified points of no return ( e.g. T =37°C, pH =4.1, c E5 =250µM, c NaCl =50mM, t >4-6 h) which will inevitably gravitate into the amyloid-state. The strong B-type FUV-ECD spectra and an unexpectedly strong NUV-ECD signal (Θ ~275-285nm ) indicate that the amyloid phase of E5 is built from monomers of quasi -elongated backbone structure ( φ ~-145°, ψ ~+145°) with strong interstrand Tyr↔Trp interaction. Misfolded intermediers and the buildup of "toxic" early-stage oligomers leading to self-association were identified and monitored as function of time. Results indicate that the amyloid transition is triggered by subtle misfolding of the α-helix exposing aromatic and hydrophobic side chains that may provide the first centers for an intermolecular reorganization. These initial clusters provide the spatial closeness and sufficient time for a transition to the β-structured amyloid nucleus thus the process follows a nucleated growth mechanism.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
Depositing User: Dóra K. Menyhárd
Date Deposited: 15 Nov 2019 12:08
Last Modified: 15 Nov 2019 12:11

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