title: A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast.
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.
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Søs G
authors.initials: SG
authors.lastname: Mathiassen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Ida B
authors.initials: IB
authors.lastname: Larsen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Esben G
authors.initials: EG
authors.lastname: Poulsen
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Madsen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Papaleo
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Birthe B
authors.initials: BB
authors.lastname: Kragelund
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nielsen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark. Electronic address: fkriegenburg@bio.ku.dk.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kriegenburg
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark. Electronic address: rhpetersen@bio.ku.dk.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Hartmann-Petersen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D003067:Coenzymes / Q000737:chemistry / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D015513:Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D000071617:Protein Deglycase DJ-1; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D003067:Coenzymes; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D066329:Protein Aggregates; D029702:Schizosaccharomyces pombe Proteins; D044767:Ubiquitin-Protein Ligases; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C546584:HSP104 protein, S pombe
keywords: Parkinson disease; Parkinson disease (autosomal recessive, early onset) 7 (PARK7); chaperone; proteasome; proteostasis; ubiquitin