A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast

Søs Grønbæk Mathiassen; Ida B. Larsen; Esben Guldahl Poulsen; Christian Toft Madsen; Elena Papaleo; Kresten Lindorff-Larsen; Birthe Brandt Kragelund; Michael Lund 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

Søs Grønbæk Mathiassen, Ida B. Larsen, Esben Guldahl Poulsen, Christian Toft Madsen, Elena Papaleo, Kresten Lindorff-Larsen, Birthe Brandt Kragelund, Michael Lund Nielsen, Franziska Kriegenburg, Rasmus Hartmann-Petersen

Biomolecular Sciences

15 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	The Journal of Biological Chemistry
Vol/bind	290
Udgave nummer	34
Sider (fra-til)	21141-21153
Antal sider	13
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.m115.662312
Status	Udgivet - 21 aug. 2015

Adgang til dokumentet

10.1074/jbc.m115.662312

http://www.jbc.org/content/290/34/21141.full.pdfLicens: CC BY

Citationsformater

Mathiassen, S. G., Larsen, I. B., Poulsen, E. G., Madsen, C. T., Papaleo, E., Lindorff-Larsen, K., Kragelund, B. B., Nielsen, M. L., Kriegenburg, F., & Hartmann-Petersen, R. (2015). A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast. The Journal of Biological Chemistry, 290(34), 21141-21153. https://doi.org/10.1074/jbc.m115.662312

@article{f61169b7736b4fd9af463ad46265dc4d,

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.",

author = "Mathiassen, {S{\o}s Gr{\o}nb{\ae}k} and Larsen, {Ida B.} and Poulsen, {Esben Guldahl} and Madsen, {Christian Toft} and Elena Papaleo and Kresten Lindorff-Larsen and Kragelund, {Birthe Brandt} and Nielsen, {Michael Lund} and Franziska Kriegenburg and Rasmus Hartmann-Petersen",

note = "{\textcopyright} 2015 by The American Society for Biochemistry and Molecular Biology, Inc.",

year = "2015",

month = aug,

day = "21",

doi = "10.1074/jbc.m115.662312",

language = "English",

volume = "290",

pages = "21141--21153",

journal = "The Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology, Inc.",

number = "34",

}

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

PY - 2015/8/21

Y1 - 2015/8/21

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

SN - 0021-9258

VL - 290

SP - 21141

EP - 21153

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 34

ER -

A two-step protein quality control pathway for a misfolded DJ-1 variant in fission yeast

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater