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Related Experiment Video

Updated: Sep 20, 2025

Utilizing Time-Resolved Protein-Induced Fluorescence Enhancement to Identify Stable Local Conformations One α-Synuclein Monomer at a Time

Utilizing Time-Resolved Protein-Induced Fluorescence Enhancement to Identify Stable Local Conformations One α-Synuclein Monomer at a Time

Published on: May 30, 2021

Conformational Switch in the Alpha-Synuclein C-Terminal Domain Directs Its Fibril Polymorphs.

Cesar Aguirre¹, Yohei Miyanoiri², Masatomo So³

¹Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Chemistry (Weinheim an Der Bergstrasse, Germany)

|May 23, 2025

Summary

Alpha-synuclein (αSyn) fibril morphology is controlled by monomer conformation. Environmental factors like calcium binding to the C-terminus act as molecular switches, influencing αSyn aggregation in neurodegenerative diseases.

Keywords:

NMR alpha synuclein amyloid fibrils fibril polymorphism protein folding proteins

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Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy

Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy

Published on: September 17, 2017

Area of Science:

Neuroscience
Biochemistry
Structural Biology

Background:

Alpha-synuclein (αSyn) inclusions are key pathological markers in synucleinopathies.
Distinct αSyn fibril polymorphs are observed, but the mechanisms controlling their formation are unclear.

Purpose of the Study:

To investigate the molecular determinants of αSyn fibril polymorphism.
To identify the role of monomeric αSyn conformation in fibril morphology.

Main Methods:

Systematic variation of ionic strength and temperature to induce fibril formation.
Solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy to analyze fibril structure.
Investigation of C-terminal domain conformational changes.

Main Results:

Two distinct αSyn polymorphs (twisted and rod-like) were generated by altering ionic strength and temperature.
Both polymorphs share a conserved core structure, with differences at protofilament interfaces.
A specific C-terminal conformational change in monomeric αSyn acts as a molecular switch for polymorphism.
Calcium binding to the C-terminus can trigger this conformational switch.

Conclusions:

Monomeric αSyn conformation, particularly in the C-terminal domain, dictates fibril morphology.
Environmental factors, such as calcium, can influence αSyn fibrogenesis by modulating C-terminal conformation.
These findings offer insights into the structural basis of synucleinopathies and potential therapeutic targets.