Journal Article

PUBDB-2026-01386

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Time‐Resolved SAXS Reveals Distinct Millisecond Metal‐Induced Conformational Dynamics of Monomeric α‐Synuclein

Sternke-Hoffmann, R. ; Pinto, M. D. S. ; Wang, X. ; Luo, J. (Corresponding author)Extern*EMBL*

2026
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/advs.202512293  doi:10.3204/PUBDB-2026-01386

Abstract: Transition metal ions have been implicated in modulation the conformational behavior and aggregation of WT α-synuclein (WT-αSyn), associated with Parkinson's disease pathology. Nevertheless, the initial structural rearrangements that drive aggregation are not fully understood. Here, we employed time-resolved small-angle X-ray scattering (TR-SAXS) in a microfluidic setup to investigate the structural dynamics of monomeric WT-αSyn upon interaction with Mn2+, Fe3+, Cu2+, and Zn2+. Using Guinier analysis, GNOM, and Ensemble Optimization Method (EOM), we resolved distinct, metal-specific conformational transitions on the sub-second timescale. Fe3+ induced rapid and sustained compaction of αSyn, while Cu2+ promoted extended and heterogeneous conformations, expanding the C-terminal domain, and disrupting global folding. In contrast, Mn2+ and Zn2+ led to more gradual, domain-specific compaction. Fractal dimension analysis and hierarchical clustering further revealed Fe3+ and Zn2+ enriched compaction states, while Cu2+ favored intermediate species potentially linked to early aggregation. These findings highlight how metal ion binding differentially and initially reshape the conformation ensemble of WT-αSyn, offering mechanistic insight into metal-induced misfolding pathways relevant to synucleinopathies.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2026

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