Characterizing methyl-bearing side chain contacts and dynamics mediating amyloid β protofibril interactions using ¹³C(methyl)-DEST and lifetime line broadening

Nicolas L. Fawzi, David S. Libich, Jinfa Ying, Vitali Tugarinov, G. Marius Clore

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Many details pertaining to the formation and interactions of protein aggregates associated with neurodegenerative diseases are invisible to conventional biophysical techniques. We recently introduced (15)N dark-state exchange saturation transfer (DEST) and (15)N lifetime line-broadening to study solution backbone dynamics and position-specific binding probabilities for amyloid β (Aβ) monomers in exchange with large (2-80 MDa) protofibrillar Aβ aggregates. Here we use (13)C(methyl)DEST and lifetime line-broadening to probe the interactions and dynamics of methyl-bearing side chains in the Aβ-protofibril-bound state. We show that all methyl groups of Aβ40 populate direct-contact bound states with a very fast effective transverse relaxation rate, indicative of side-chain-mediated direct binding to the protofibril surface. The data are consistent with position-specific enhancements of (13)C(methyl)-R₂(tethered) values in tethered states, providing further insights into the structural ensemble of the protofibril-bound state.

Original languageEnglish (US)
Pages (from-to)10345-10349
Number of pages5
JournalAngewandte Chemie (International ed. in English)
Volume53
Issue number39
DOIs
StatePublished - Sep 22 2014
Externally publishedYes

Keywords

  • NMR spectroscopy
  • amyloid β
  • high-molecular-weight assemblies
  • protein-protein interactions

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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