Probing initial transient oligomerization events facilitating Huntingtin fibril nucleation at atomic resolution by relaxation-based NMR.

ABSTRACT: The N-terminal region of the huntingtin protein, encoded by exon-1, comprises an amphiphilic domain (htt^NT), a polyglutamine (Q _n ) tract, and a proline-rich sequence. Polyglutamine expansion results in an aggregation-prone protein responsible for Huntington's disease. Here, we study the earliest events involved in oligomerization of a minimalistic construct, htt^NTQ₇, which remains largely monomeric over a sufficiently long period of time to permit detailed quantitative NMR analysis of the kinetics and structure of sparsely populated [Formula: see text] oligomeric states, yet still eventually forms fibrils. Global fitting of concentration-dependent relaxation dispersion, transverse relaxation in the rotating frame, and exchange-induced che

SUBMITTER: Kotler SA 

PROVIDER: S-EPMC6397591 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature