期刊
CHEMBIOCHEM
卷 23, 期 21, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202200396
关键词
amyotrophic lateral sclerosis; CLR01; SOD1; medicinal chemistry; supramolecular ligands
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany.s Excellence Strategy [EXC 2033-390677874 -RESOLV]
- Programm Forschungsgrossgerate [436586093, 423465882]
- GIF [1410]
- German Research Foundation DFG-SPP 2191 Molecular Mechanisms of Functional Phase Separation [402723784]
- IGSN
- DFG [A8]
- US National Institutes of Health [R01GM103479, S10RR028893]
- US Department of Energy [DE-FC02-02ER63421]
- Ruth L. Kirschstein National Research Service Award program [GM007185]
- Projekt DEAL
Protein misfolding and aggregation are common features of many neurodegenerative diseases. This study investigates the modulation mechanism of the unfolding and aggregation pathways of SOD1 protein, which is involved in ALS, by the supramolecular ligand CLR01. The results provide insights into the molecular mechanisms of how CLR01 affects the stability of SOD1 and suggest it as a potential target for the development of drugs against neurodegenerative diseases.
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, SOD1(bar), we show that CLR01 acts on the first step of the aggregation pathway, the unfolding of the SOD1 monomer. CLR01 increases, by similar to 10 degrees 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.
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