Abrogation of prenucleation, transient oligomerization of the Huntingtin exon 1 protein by human profilin I
Abstract
Polyglutamine expansion within the N-terminal region of huntingtin encoded by exon 1 (httex1) results in accumulation of httex1 aggregates in neurons, leading to Huntington's disease. Profilin is a ubiquitous intracellular protein that reduces aggregation and toxicity of httex1. Prenucleation, transient oligomerization of the httex1 N-terminal amphiphilic domain proceeds along two branches: an on-pathway, "productive" branch resulting in a helical coiled-coil tetramer that supports nucleation of the polyglutamine tract and subsequent aggregation, and an off-pathway "nonproductive" branch that does not proceed beyond a partially helical dimer. Using NMR, we show that profilin binding to the proline-rich domain of httex1 blocks the on-pathway oligomerization pathway while leaving the off-pathway branch unaffected, thereby providing a mechanistic basis for profilin inhibition of httex1 aggregation.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- March 2020
- DOI:
- 10.1073/pnas.1922264117
- Bibcode:
- 2020PNAS..117.5844C