1H NMR of Aβ Amyloid Peptide Congeners in Water Solution. Conformational Changes Correlate with Plaque Competence

Jonathan P. Lee, Evelyn R. Stimson, John E. Maggio, Joseph R. Ghilardi, Patrick W. Mantyh, Yi An Lu, Arthur M. Felix, William Llanos, Ali Behbin, Mike Cummings, Mark Van Criekinge, William Timms

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

To begin to examine the structural basis for the deposition of soluble A/β amyloid peptide onto senile plaques in Alzheimer's disease, we have prepared A/β congeners and measured their activity in an in vitro plaque growth assay. The N-terminal fragment, A/β(l-28)-OH, was inactive at all pH values tested. While the central fragment, A/β(10-35)-NH2, and the full length peptide, A/β(l-40)-C)H, were inactive below pH 4, both were active (plaque competent) between pH 5 and 9. The active and inactive fragments were studied by nuclear magnetic resonance spectroscopy in water at submillimolar concentrations at pH 2.1 and 5.6. Changes in chemical shifts, coupling constants, and nuclear Overhauser enhancements indicate a pH dependent folding transition in A/β(10-35)-NH2 as it becomes active. The conformation of the active fragment is not helical, and preliminary data indicate the presence of several turns and at least two short strands. In contrast, the inactive fragment A/β(l-28)-OH did not undergo a similar folding transition. Earlier nuclear magnetic resonance studies of amyloid peptides in fluorinated alcohols or detergent micelles at low pH described a helical conformation and proposed a helix to sheet transition in plaque formation; the present study demonstrates that no such conformations are present in water under conditions where the peptides can adhere to authentic amyloid plaques.

Original languageEnglish (US)
Pages (from-to)5191-5200
Number of pages10
JournalBiochemistry
Volume34
Issue number15
DOIs
StatePublished - Apr 1 1995
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Lee, J. P., Stimson, E. R., Maggio, J. E., Ghilardi, J. R., Mantyh, P. W., Lu, Y. A., Felix, A. M., Llanos, W., Behbin, A., Cummings, M., Van Criekinge, M., & Timms, W. (1995). 1H NMR of Aβ Amyloid Peptide Congeners in Water Solution. Conformational Changes Correlate with Plaque Competence. Biochemistry, 34(15), 5191-5200. https://doi.org/10.1021/bi00015a033