A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast
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A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast. / Mathiassen, Søs Grønbæk; Larsen, Ida B.; Poulsen, Esben Guldahl; Madsen, Christian Toft; Papaleo, Elena; Lindorff-Larsen, Kresten; Kragelund, Birthe Brandt; Nielsen, Michael Lund; Kriegenburg, Franziska; Hartmann-Petersen, Rasmus.
In: The Journal of Biological Chemistry, Vol. 290, No. 34, 2015, p. 21141-21153.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast
AU - Mathiassen, Søs Grønbæk
AU - Larsen, Ida B.
AU - Poulsen, Esben Guldahl
AU - Madsen, Christian Toft
AU - Papaleo, Elena
AU - Lindorff-Larsen, Kresten
AU - Kragelund, Birthe Brandt
AU - Nielsen, Michael Lund
AU - Kriegenburg, Franziska
AU - Hartmann-Petersen, Rasmus
N1 - © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1074/jbc.M115.662312
DO - 10.1074/jbc.M115.662312
M3 - Journal article
C2 - 26152728
VL - 290
SP - 21141
EP - 21153
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 34
ER -
ID: 143918956