Abstract
A mutation, L166P, in the cytosolic protein, PARK7/DJ-1, causes protein misfolding and is linked to Parkinson disease. Here, we identify the fission yeast protein Sdj1 as the orthologue of DJ-1 and calculate by in silico saturation mutagenesis the effects of point mutants on its structural stability. We also map the degradation pathways for Sdj1-L169P, the fission yeast orthologue of the disease-causing DJ-1 L166P protein. Sdj1-L169P forms inclusions, which are enriched for the Hsp104 disaggregase. Hsp104 and Hsp70-type chaperones are required for efficient degradation of Sdj1-L169P. This also depends on the ribosome-associated E3 ligase Ltn1 and its co-factor Rqc1. Although Hsp104 is absolutely required for proteasomal degradation of Sdj1-L169P aggregates, the degradation of already aggregated Sdj1-L169P occurs independently of Ltn1 and Rqc1. Thus, our data point to soluble Sdj1-L169P being targeted early by Ltn1 and Rqc1. The fraction of Sdj1-L169P that escapes this first inspection then forms aggregates that are subsequently cleared via an Hsp104- and proteasome-dependent pathway.
Highlights
A mutation, L166P, in DJ-1, is linked to Parkinson disease
Sdj1 Is the Fission Orthologue of Human DJ-1—In a database search for proteins involved in stress response and proteostasis, we noticed that the S. pombe SPAC22E12.03c protein was highly similar to the human Parkinson disease protein PARK7/ DJ-1
Because the accumulation of misfolded proteins has been linked to a variety of human diseases [48], the quality control mechanisms that govern their turnover have been the subject to intense investigation [3, 49]
Summary
Results: The Sdj1-L169P fission yeast orthologue of DJ1-L166P is misfolded, associated with chaperones, and degraded via two ubiquitin-proteasome dependent pathways. We map the degradation pathways for Sdj1-L169P, the fission yeast orthologue of the disease-causing DJ-1 L166P protein. Hsp104 and Hsp70-type chaperones are required for efficient degradation of Sdj1-L169P This depends on the ribosome-associated E3 ligase Ltn and its co-factor Rqc. In the absence of stress, protein misfolding may occur as a result of mutation or defects in synthesis, intracellular trafficking, or association with other macromolecules If such partially denatured proteins are not efficiently eliminated, they can form. The protein is rapidly degraded by the proteasome through a pathway that depends on the Hsp70type chaperone Ssa, the Hsp104 disaggregase, and the ribosome-associated E3 ubiquitin-protein ligase Ltn. The fraction that escapes this first inspection continues to form cytosolic aggregates, which are cleared via an Hsp104- and proteasomedependent pathway
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