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Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
Ligand binding and aggregation of pathogenic SOD1
Gareth S A Wright1, Svetlana V Antonyuk, Neil M Kershaw
1Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK.
Nature Communications
|April 25, 2013
Summary
Mutations in copper-zinc superoxide dismutase-1 (SOD1) cause ALS. This study reveals that SOD1 stabilizers interact with an aggregate core, not the dimer interface, highlighting the need for structural insights in drug development.
Area of Science:
- Biochemistry
- Neuroscience
- Structural Biology
Background:
- Mutations in copper-zinc superoxide dismutase-1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS).
- SOD1 mutations destabilize the protein, leading to aggregation, with the monomeric form potentially acting as an intermediate.
- Stabilizing the SOD1 dimer and preventing aggregation are pursued as therapeutic strategies for ALS.
Purpose of the Study:
- To investigate the structural perturbations of monomeric copper-apo, zinc-holo SOD1.
- To identify the specific binding sites of potential SOD1 stabilizers, Isoproterenol and 5-fluorouridine.
- To assess the implications of binding site identification for developing targeted therapeutics.
Main Methods:
- Characterization of monomeric copper-apo, zinc-holo SOD1 structure and aggregation propensity.
- Analysis of protein-ligand interactions between SOD1 and Isoproterenol/5-fluorouridine.
- Structural identification of ligand binding sites within SOD1.
Main Results:
- Monomeric copper-apo, zinc-holo SOD1 exhibits structural perturbations and aggregates without restoring monomer-dimer equilibrium.
- Isoproterenol and 5-fluorouridine bind to SOD1 at a region within the core of fibrillar aggregates (β-barrel loop II-strand 3).
- Ligand binding does not occur at the previously proposed dimer interface site.
Conclusions:
- Direct structural evidence reveals that SOD1 stabilizers bind to an aggregate-related site, not the dimer interface.
- This finding underscores the critical importance of direct structural studies for designing effective protein-targeted ALS therapeutics.
- Understanding the precise interaction sites is crucial for optimizing drug design and efficacy.
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