Quantitative Exchange NMR-Based Analysis of Huntingtin-SH3 Interactions Suggests an Allosteric Mechanism of Inhibition of Huntingtin Aggregation.

ABSTRACT: Huntingtin polypeptides (htt^ex1), encoded by exon 1 of the htt gene and containing an expanded polyglutamine tract, form fibrils that accumulate within neuronal inclusion bodies, resulting in the fatal neurodegenerative condition known as Huntington's disease. Htt^ex1 comprises three regions: a 16-residue N-terminal amphiphilic domain (NT), a polyglutamine tract of variable length (Q_n), and a polyproline-rich domain containing two polyproline tracts. The NT region of htt^ex1 undergoes prenucleation transient oligomerization on the sub-millisecond time scale, resulting in a productive tetramer that promotes self-association and nucleation of the polyglutamine tracts. Here we show that binding of Fyn SH3, a small intracellular proline-b

SUBMITTER: Ceccon A 

PROVIDER: S-EPMC8855710 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature