Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins

Chemical Science
Gaetano MalgieriRoberto Fattorusso

Abstract

Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml153-149 and zinc-lacking Ml452-151. The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml153-149 appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml452-151 folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml452-151 and Ml153-149 to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml153-149 has formed only amorphous aggregates and Ml452-151 is still monomeric in solution. This study shows how metal binding can influen...Continue Reading

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Citations

Jun 11, 2020·Scientific Reports·Gianluca D'AbroscaGaetano Malgieri
Dec 5, 2020·Scientific Reports·Rinaldo GraziosoGaetano Malgieri
Apr 15, 2021·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·Erwan Y DarussalamVolker Deckert
Feb 25, 2019·International Journal of Biological Macromolecules·L PironeE Pedone
Oct 25, 2021·The FEBS Journal·Donatella DianaRoberto Fattorusso

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Methods Mentioned

BETA
protein folding
circular
dynamic
scanning electron microscopies
electrophoresis
NMR

Software Mentioned

MicroCal
Malvern
AGGRESCAN

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