Abstract
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute 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 diseases, irrespective of the specific misfolded protein that is involved.
Highlights
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin–proteasome system plays a major role in protein degradation and proteostasis
Impairment of the 26S proteasome demonstrates that the oligomers must bind to the 20S even in the presence of the 19S, as was observed for the PA26–20S complexes, demonstrating that the oligomers likely bind to the outer surface of the 20S proteasome supporting the hypothesis that these toxic oligomers act allosterically preventing the 20S gate from opening properly. Since these results clearly demonstrate that A11+ oligomers are able to impair the 20S core particle by itself, it is most likely that their impairment of the 26S proteasome is via the same mechanism, acting on the core particle
The substrate-entry gate in the 20S proteasome plays a critical role in proteasome function and in cellular proteostasis
Summary
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin–proteasome system plays a major role in protein degradation and proteostasis. 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 diseases, irrespective of the specific misfolded protein that is involved. One study has been able to show that heterogeneous aggregates of the mouse prion protein, PrPsc, reduced substrate entry by decreasing proteasomal gating[36] Despite these many efforts, an understanding of why and how the proteasome is so generally impaired in neurodegenerative disease has remained elusive. Regulation of the 20S proteasome gate is an important aspect of proteasome function and the cell has evolved many different proteasomal regulators that control 20S gate opening, many of which contain the HbYX motif (e.g., the 19S ATPases: Rpt[2], Rpt[3], Rpt[5]; Blm10/PA200; Pba1–Pba[2]; PI31; and archaeal CDC48/P97), and some that do not (i.e., the 11S family: PA28αβ and PA26)[48]
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