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Binding structures of SERF1a with NT17-polyQ peptides of huntingtin exon 1 revealed by SEC-SWAXS, NMR and molecular simulation

Authors :
Tien-Chang Lin
Orion Shih
Tien-Ying Tsai
Yi-Qi Yeh
Kuei-Fen Liao
Bradley W. Mansel
Ying-Jen Shiu
Chi-Fon Chang
An-Chung Su
Yun-Ru Chen
U-Ser Jeng
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