The inhibitory action of the chaperone BRICHOS against the α-Synuclein secondary nucleation pathway

Dhiman Ghosh, Felix Torres, Matthias M. Schneider, Dzmitry Ashkinadze, Harindranath Kadavath, Yanick Fleischmann, Simon Mergenthal, Peter Güntert, Georg Krainer, Ewa A. Andrzejewska, Lily Lin, Jiapeng Wei, Enrico Klotzsch (), Tuomas Knowles () and Roland Riek ()
Additional contact information
Dhiman Ghosh: ETH Zürich, Vladimir-Prelog-Weg 2
Felix Torres: ETH Zürich, Vladimir-Prelog-Weg 2
Matthias M. Schneider: University of Cambridge, Lensfield Road
Dzmitry Ashkinadze: ETH Zürich, Vladimir-Prelog-Weg 2
Harindranath Kadavath: ETH Zürich, Vladimir-Prelog-Weg 2
Yanick Fleischmann: ETH Zürich, Vladimir-Prelog-Weg 2
Simon Mergenthal: Experimental Biophysics / Mechanobiology, Humboldt-Universität zu Berlin
Peter Güntert: ETH Zürich, Vladimir-Prelog-Weg 2
Georg Krainer: University of Cambridge, Lensfield Road
Ewa A. Andrzejewska: University of Cambridge, Lensfield Road
Lily Lin: University of Cambridge, Lensfield Road
Jiapeng Wei: University of Cambridge, Lensfield Road
Enrico Klotzsch: Experimental Biophysics / Mechanobiology, Humboldt-Universität zu Berlin
Tuomas Knowles: University of Cambridge, Lensfield Road
Roland Riek: ETH Zürich, Vladimir-Prelog-Weg 2

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The complex kinetics of disease-related amyloid aggregation of proteins such as α-Synuclein (α-Syn) in Parkinson’s disease and Aβ42 in Alzheimer’s disease include primary nucleation, amyloid fibril elongation and secondary nucleation. The latter can be a key accelerator of the aggregation process. It has been demonstrated that the chaperone domain BRICHOS can interfere with the secondary nucleation process of Aβ42. Here, we explore the mechanism of secondary nucleation inhibition of the BRICHOS domain of the lung surfactant protein (proSP-C) against α-Syn aggregation and amyloid formation. We determine the 3D NMR structure of an inactive trimer of proSP-C BRICHOS and its active monomer using a designed mutant. Furthermore, the interaction between the proSP-C BRICHOS chaperone and a substrate peptide has been studied. NMR-based interaction studies of proSP-C BRICHOS with α-Syn fibrils show that proSP-C BRICHOS binds to the C-terminal flexible fuzzy coat of the fibrils, which is the secondary nucleation site on the fibrils. Super-resolution fluorescence microscopy demonstrates that proSP-C BRICHOS runs along the fibrillar axis diffusion-dependently sweeping off monomeric α-Syn from the fibrils. The observed mechanism explains how a weakly binding chaperone can inhibit the α-Syn secondary nucleation pathway via avidity where a single proSP-C BRICHOS molecule is sufficient against up to ~7-40 α-Syn molecules embedded within the fibrils.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54212-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54212-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54212-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().