Document Type
Article
Publication Date
2018
College/Unit
School of Medicine
Department/Program/Center
Biochemistry
Abstract
Protein accumulation and aggregation with a concomitant loss of proteostasis often con- tribute to neurodegenerative diseases, and the ubiquitin–proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer’s, Parkinson’s, and Huntington’s disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative dis- eases, irrespective of the specific misfolded protein that is involved.
Digital Commons Citation
Thibaudeau, Tiffany A.; Anderson, Raymond T.; and Smith, David M., "A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers" (2018). Faculty & Staff Scholarship. 1732.
https://researchrepository.wvu.edu/faculty_publications/1732
Source Citation
Thibaudeau, T. A., Anderson, R. T., & Smith, D. M. (2018). A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-03509-0
Comments
Open Access This article is licensed under a Creative Commons
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© The Author(s) 2018