A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast

Søs 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

doi:10.1074/jbc.M115.662312

A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast

J Biol Chem. 2015 Aug 21;290(34):21141-21153. doi: 10.1074/jbc.M115.662312. Epub 2015 Jul 7.

Affiliations

¹ Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
² Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
³ Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark. Electronic address: [email protected].
⁴ Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark. Electronic address: [email protected].

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: Parkinson disease; Parkinson disease (autosomal recessive, early onset) 7 (PARK7); chaperone; proteasome; proteostasis; ubiquitin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism*
Amino Acid Sequence
Coenzymes / chemistry
Coenzymes / metabolism*
HSP70 Heat-Shock Proteins / genetics
HSP70 Heat-Shock Proteins / metabolism*
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / chemistry*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Models, Molecular
Molecular Sequence Data
Mutation
Oncogene Proteins / chemistry*
Oncogene Proteins / genetics
Oncogene Proteins / metabolism
Proteasome Endopeptidase Complex / metabolism
Protein Aggregates
Protein Deglycase DJ-1
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Proteolysis
Schizosaccharomyces / genetics
Schizosaccharomyces / metabolism*
Schizosaccharomyces pombe Proteins / chemistry*
Schizosaccharomyces pombe Proteins / genetics
Schizosaccharomyces pombe Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Coenzymes
HSP70 Heat-Shock Proteins
Heat-Shock Proteins
Intracellular Signaling Peptides and Proteins
Oncogene Proteins
Protein Aggregates
Schizosaccharomyces pombe Proteins
Ubiquitin-Protein Ligases
PARK7 protein, human
Protein Deglycase DJ-1
Proteasome Endopeptidase Complex
Adenosine Triphosphatases
HSP104 protein, S pombe

Associated data

PDB/4QYT