A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast |
| |
| Authors: | S?s G Mathiassen Ida B Larsen Esben G Poulsen Christian T Madsen Elena Papaleo Kresten Lindorff-Larsen Birthe B Kragelund Michael L Nielsen Franziska Kriegenburg Rasmus Hartmann-Petersen |
| |
| Institution: | From the ‡Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N and ;§The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark |
| |
| 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. |
| |
| Keywords: | chaperone Parkinson disease Parkinson disease (autosomal recessive early onset) 7 (PARK7) proteasome proteostasis ubiquitin |
|
|
