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Transient Diffusive Interactions with a Protein Crowder Affect Aggregation Processes of Superoxide Dismutase 1
Naoto Iwakawa1, Daichi Morimoto1, Erik Walinda2
1Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
The Journal of Physical Chemistry. B
|March 3, 2021
Summary
Protein crowding, like that found inside cells, can slow down the aggregation of superoxide dismutase 1 (SOD1), a key factor in amyotrophic lateral sclerosis (ALS). This suggests the cellular environment may inhibit protein aggregation relevant to neurodegenerative diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Amyotrophic lateral sclerosis (ALS) is linked to the aggregation of superoxide dismutase 1 (SOD1) within motor neurons.
- Cellular environments can decrease the thermodynamic stability of the SOD1 β-barrel.
- The relationship between crowding-induced protein destabilization and SOD1 aggregation is not fully understood.
Purpose of the Study:
- To investigate the impact of a protein crowder, lysozyme, on SOD1 β-barrel fibril aggregate formation.
- To elucidate the thermodynamic mechanisms by which cellular crowding affects SOD1 aggregation.
Main Methods:
- Examined the effects of lysozyme as a protein crowder on SOD1 aggregate formation in vitro.
- Analyzed the structural and dynamic changes of SOD1 in crowded solutions using biophysical techniques.
Main Results:
- Aggregate formation of SOD1 was decelerated in mildly crowded solutions.
- Lysozyme interactions did not significantly alter the static structure of the SOD1 β-barrel.
- Crowding stabilized an alternative, non-aggregating "invisible" state of SOD1, favoring species off the aggregation pathway.
Conclusions:
- Cellular crowding can inhibit SOD1 aggregation by stabilizing non-aggregating protein states.
- These findings suggest that intracellular environments may generally inhibit fibril formation of other amyloidogenic proteins.
- Understanding crowding effects on protein aggregation is crucial for elucidating the etiology of neurodegenerative diseases.
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