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Binding structures of SERF1a with NT17-polyQ peptides of huntingtin exon 1 revealed by SEC-SWAXS, NMR and molecular simulation
- Source :
- IUCrJ, Vol 11, Iss 5, Pp 849-858 (2024)
- Publication Year :
- 2024
- Publisher :
- International Union of Crystallography, 2024.
-
Abstract
- The aberrant fibrillization of huntingtin exon 1 (Httex1) characterized by an expanded polyglutamine (polyQ) tract is a defining feature of Huntington's disease, a neurodegenerative disorder. Recent investigations underscore the involvement of a small EDRK-rich factor 1a (SERF1a) in promoting Httex1 fibrillization through interactions with its N terminus. By establishing an integrated approach with size-exclusion-column-based small- and wide-angle X-ray scattering (SEC-SWAXS), NMR, and molecular simulations using Rosetta, the analysis here reveals a tight binding of two NT17 fragments of Httex1 (comprising the initial 17 amino acids at the N terminus) to the N-terminal region of SERF1a. In contrast, examination of the complex structure of SERF1a with a coiled NT17-polyQ peptide (33 amino acids in total) indicates sparse contacts of the NT17 and polyQ segments with the N-terminal side of SERF1a. Furthermore, the integrated SEC-SWAXS and molecular-simulation analysis suggests that the coiled NT17 segment can transform into a helical conformation when associated with a polyQ segment exhibiting high helical content. Intriguingly, NT17-polyQ peptides with enhanced secondary structures display diminished interactions with SERF1a. This insight into the conformation-dependent binding of NT17 provides clues to a catalytic association mechanism underlying SERF1a's facilitation of Httext1 fibrillization.
Details
- Language :
- English
- ISSN :
- 20522525
- Volume :
- 11
- Issue :
- 5
- Database :
- Directory of Open Access Journals
- Journal :
- IUCrJ
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.209dc44d9cfb417082cdde097083b7a8
- Document Type :
- article
- Full Text :
- https://doi.org/10.1107/S2052252524006341