Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43
| Autor: | Ivan S. Podkorytov, Adam Groves, Dmitrii A. Luzik, Sevastyan O. Rabdano, Nikolai R. Skrynnikov, Sergei A. Izmailov |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Folding Magnetic Resonance Spectroscopy Protein Conformation Proteolysis lcsh:Medicine Protein aggregation Protein Aggregation Pathological Dithiothreitol Article 03 medical and health sciences chemistry.chemical_compound Protein Aggregates Structure-Activity Relationship Protein structure Dynamic light scattering medicine Humans Protein Interaction Domains and Motifs Disulfides lcsh:Science Multidisciplinary medicine.diagnostic_test Chemistry lcsh:R Nuclear magnetic resonance spectroscopy Hydrogen Peroxide DNA-Binding Proteins 030104 developmental biology Monomer Biophysics Protein folding lcsh:Q Disease Susceptibility Protein Multimerization Oxidation-Reduction Algorithms Protein Binding |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-20 (2017) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | We have investigated the behavior of second RNA-recognition motif (RRM2) of neuropathological protein TDP43 under the effect of oxidative stress as modeled in vitro. Toward this end we have used the specially adapted version of H/D exchange experiment, NMR relaxation and diffusion measurements, dynamic light scattering, controlled proteolysis, gel electrophoresis, site-directed mutagenesis and microsecond MD simulations. Under oxidizing conditions RRM2 forms disulfide-bonded dimers that experience unfolding and then assemble into aggregate particles (APs). These particles are strongly disordered, highly inhomogeneous and susceptible to proteolysis; some of them withstand the dithiothreitol treatment. They can recruit/release monomeric RRM2 through thiol-disulfide exchange reactions. By using a combination of dynamic light scattering and NMR diffusion data we were able to approximate the size distribution function for the APs. The key to the observed aggregation behavior is the diminished ability of disulfide-bonded RRM2 dimers to refold and their increased propensity to misfold, which makes them vulnerable to large thermal fluctuations. The emerging picture provides detailed insight on how oxidative stress can contribute to neurodegenerative disease, with unfolding, aggregation, and proteolytic cleavage as different facets of the process. |
| Databáze: | OpenAIRE |
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