Gly25-Ser26 amyloid ?-protein structural isomorphs produce distinct A?42 conformational dynamics and assembly characteristics.

ABSTRACT: One of the earliest events in amyloid ?-protein (A?) self-association is nucleation of A? monomer folding through formation of a turn at Gly25-Lys28. We report here the effects of structural changes at the center of the turn, Gly25-Ser26, on A?42 conformational dynamics and assembly. We used "click peptide" chemistry to quasi-synchronously create A?42 from 26-O-acyliso-A?42 (iA?42) through a pH jump from 3 to 7.4. We also synthesized N?-acetyl-Ser26-iA?42 (Ac-iA?42), which cannot undergo O?N acyl chemistry, to study the behavior of this ester form of A?42 itself at neutral pH. Data from experiments monitoring increases in ?-sheet formation (thioflavin T, CD), hydrodynamic radius (RH), scattering intensity (quasielastic light scattering spectroscopy), and extent of oligomerization (ion mobility spectroscopy-mass spectrometry) were quite consistent. A rank order of Ac-iA?42>iA?42>A?42 was observed. Photochemically cross-linked iA?42 displayed an oligomer distribution with a prominent dimer band that was not present with A?42. These dimers also were observed selectively in iA?42 in ion mobility spectrometry experiments. The distinct biophysical behaviors of iA?42 and A?42 appear to be due to the conversion of iA?42 into "pure" A?42 monomer, a nascent form of A?42 that does not comprise the variety of oligomeric and aggregated states present in pre-existent A?42. These results emphasize the importance of the Gly25-Ser26 dipeptide in organizing A?42 monomer structure and thus suggest that drugs altering the interactions of this dipeptide with neighboring side-chain atoms or with the peptide backbone could be useful in therapeutic strategies targeting formation of A? oligomers and higher-order assemblies.

SUBMITTER: Roychaudhuri R 

PROVIDER: S-EPMC4191920 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature