title: Gly25-Ser26 amyloid β-protein structural isomorphs produce distinct Aβ42 conformational dynamics and assembly characteristics.
abstract: One of the earliest events in amyloid β-protein (Aβ) self-association is nucleation of Aβ 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 Aβ42 conformational dynamics and assembly. We used "click peptide" chemistry to quasi-synchronously create Aβ42 from 26-O-acyliso-Aβ42 (iAβ42) through a pH jump from 3 to 7.4. We also synthesized Nα-acetyl-Ser26-iAβ42 (Ac-iAβ42), which cannot undergo O→N acyl chemistry, to study the behavior of this ester form of Aβ42 itself at neutral pH. Data from experiments monitoring increases in β-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-iAβ42>iAβ42>Aβ42 was observed. Photochemically cross-linked iAβ42 displayed an oligomer distribution with a prominent dimer band that was not present with Aβ42. These dimers also were observed selectively in iAβ42 in ion mobility spectrometry experiments. The distinct biophysical behaviors of iAβ42 and Aβ42 appear to be due to the conversion of iAβ42 into "pure" Aβ42 monomer, a nascent form of Aβ42 that does not comprise the variety of oligomeric and aggregated states present in pre-existent Aβ42. These results emphasize the importance of the Gly25-Ser26 dipeptide in organizing Aβ42 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 Aβ oligomers and higher-order assemblies.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Roychaudhuri
authors.affiliation: Department of Physics and Center for Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Lomakin
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Summer
authors.initials: S
authors.lastname: Bernstein
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Condron
authors.affiliation: Department of Physics and Center for Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: Benedek
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bowers
authors.affiliation: Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute and Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dteplow@ucla.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000648:ultrastructure; D055592:Biophysical Phenomena; D057930:Click Chemistry; D005998:Glycine / Q000737:chemistry; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000648:ultrastructure; D011487:Protein Conformation; D017510:Protein Folding; D020033:Protein Isoforms / Q000138:chemical synthesis / Q000737:chemistry / Q000648:ultrastructure; D055503:Protein Multimerization; D012694:Serine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42); D012694:Serine; D005998:Glycine
keywords: Alzheimer's disease; amyloid β-protein; fibril formation; ion mobility spectroscopy–mass spectrometry; oligomerization
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