1. Superoxide Dismutase 1 Folding Stability as a Target for Molecular Tweezers in SOD1‐Related Amyotrophic Lateral Sclerosis
- Author
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Samanta, Nirnay, Ruiz‐Blanco, Yasser B, Fetahaj, Zamira, Gnutt, David, Lantz, Carter, Loo, Joseph A, Sanchez‐Garcia, Elsa, and Ebbinghaus, Simon
- Subjects
Biochemistry and Cell Biology ,Chemical Sciences ,Biological Sciences ,Neurodegenerative ,Nanotechnology ,Rare Diseases ,Bioengineering ,Brain Disorders ,Neurosciences ,ALS ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Aetiology ,Development of treatments and therapeutic interventions ,Neurological ,Humans ,Superoxide Dismutase-1 ,Amyotrophic Lateral Sclerosis ,Superoxide Dismutase ,Protein Folding ,Mutation ,Neurodegenerative Diseases ,amyotrophic lateral sclerosis ,CLR01 ,SOD1 ,medicinal chemistry ,supramolecular ligands ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
Protein misfolding and aggregation are hallmarks of many severe neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease. As a supramolecular ligand that binds to lysine and arginine residues, the molecular tweezer CLR01 was found to modify the aggregation pathway of disease-relevant proteins in vitro and in vivo with beneficial effects on toxicity. However, the molecular mechanisms of how tweezers exert these effects remain mainly unknown, hampering further drug development. Here, we investigate the modulation mechanism of unfolding and aggregation pathways of SOD1, which are involved in amyotrophic lateral sclerosis (ALS), by CLR01. Using a truncated version of the wildtype SOD1 protein, SOD1bar , we show that CLR01 acts on the first step of the aggregation pathway, the unfolding of the SOD1 monomer. CLR01 increases, by ∼10 °C, the melting temperatures of the A4V and G41D SOD1 mutants, which are commonly observed mutations in familial ALS. Molecular dynamics simulations and binding free energy calculations as well as native mass spectrometry and mutational studies allowed us to identify K61 and K92 as binding sites for the tweezers to mediate the stability increase. The data suggest that the modulation of SOD1 conformational stability is a promising target for future developments of supramolecular ligands against neurodegenerative diseases.
- Published
- 2022