L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner

Yasuhiro Moriwaki, Yeon Jeong Kim, Yukari Ido, Hidemi Misawa, Koichiro Kawashima, Shogo Endo, Ryosuke Takahashi

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Mutation of PTEN-induced kinase 1 (PINK1), which encodes a putative mitochondrial serine/threonine kinase, leads to PARK6, an autosomal recessive form of familial Parkinson's disease. Although the precise function(s) of PINK1 protein is unknown, the recessive inheritance of this form of Parkinson's disease suggests loss of PINK1 function is closely associated with its pathogenesis. Here we report that PINK1 forms a complex with the molecular chaperones Hsp90 and Cdc37/p50 within cells, which appears to enhance its stability. When cells were treated with an Hsp90 inhibitor (geldanamycin or novobiocin), levels of PINK1 were greatly diminished, reflecting its rapid degradation via ubiquitin-proteasome pathway. Similarly, the half-life of a pathogenic PINK1 mutant (L347P) that did not interact with Hsp90 or Cdc37/p50 was only 30 min, whereas that of wild-type PINK1 was 1 h. These results strongly suggest that Hsp90 and Cdc37 are binding partners of PINK1 which regulate its stability.

Original languageEnglish
Pages (from-to)43-48
Number of pages6
JournalNeuroscience Research
Volume61
Issue number1
DOIs
Publication statusPublished - 2008 May

Fingerprint

Proteasome Endopeptidase Complex
Phosphotransferases
Novobiocin
Molecular Chaperones
Protein-Serine-Threonine Kinases
Parkinsonian Disorders
Ubiquitin
Protein Kinases
Parkinson Disease
Half-Life
Mutation

Keywords

  • Cdc37
  • Hsp90
  • Parkinson's disease
  • PINK1
  • Proteasome
  • Stability

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner. / Moriwaki, Yasuhiro; Kim, Yeon Jeong; Ido, Yukari; Misawa, Hidemi; Kawashima, Koichiro; Endo, Shogo; Takahashi, Ryosuke.

In: Neuroscience Research, Vol. 61, No. 1, 05.2008, p. 43-48.

Research output: Contribution to journalArticle

Moriwaki, Yasuhiro ; Kim, Yeon Jeong ; Ido, Yukari ; Misawa, Hidemi ; Kawashima, Koichiro ; Endo, Shogo ; Takahashi, Ryosuke. / L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner. In: Neuroscience Research. 2008 ; Vol. 61, No. 1. pp. 43-48.
@article{ef547668dc9c4065a5d483c6a3f3ede7,
title = "L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner",
abstract = "Mutation of PTEN-induced kinase 1 (PINK1), which encodes a putative mitochondrial serine/threonine kinase, leads to PARK6, an autosomal recessive form of familial Parkinson's disease. Although the precise function(s) of PINK1 protein is unknown, the recessive inheritance of this form of Parkinson's disease suggests loss of PINK1 function is closely associated with its pathogenesis. Here we report that PINK1 forms a complex with the molecular chaperones Hsp90 and Cdc37/p50 within cells, which appears to enhance its stability. When cells were treated with an Hsp90 inhibitor (geldanamycin or novobiocin), levels of PINK1 were greatly diminished, reflecting its rapid degradation via ubiquitin-proteasome pathway. Similarly, the half-life of a pathogenic PINK1 mutant (L347P) that did not interact with Hsp90 or Cdc37/p50 was only 30 min, whereas that of wild-type PINK1 was 1 h. These results strongly suggest that Hsp90 and Cdc37 are binding partners of PINK1 which regulate its stability.",
keywords = "Cdc37, Hsp90, Parkinson's disease, PINK1, Proteasome, Stability",
author = "Yasuhiro Moriwaki and Kim, {Yeon Jeong} and Yukari Ido and Hidemi Misawa and Koichiro Kawashima and Shogo Endo and Ryosuke Takahashi",
year = "2008",
month = "5",
doi = "10.1016/j.neures.2008.01.006",
language = "English",
volume = "61",
pages = "43--48",
journal = "Neuroscience Research",
issn = "0168-0102",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner

AU - Moriwaki, Yasuhiro

AU - Kim, Yeon Jeong

AU - Ido, Yukari

AU - Misawa, Hidemi

AU - Kawashima, Koichiro

AU - Endo, Shogo

AU - Takahashi, Ryosuke

PY - 2008/5

Y1 - 2008/5

N2 - Mutation of PTEN-induced kinase 1 (PINK1), which encodes a putative mitochondrial serine/threonine kinase, leads to PARK6, an autosomal recessive form of familial Parkinson's disease. Although the precise function(s) of PINK1 protein is unknown, the recessive inheritance of this form of Parkinson's disease suggests loss of PINK1 function is closely associated with its pathogenesis. Here we report that PINK1 forms a complex with the molecular chaperones Hsp90 and Cdc37/p50 within cells, which appears to enhance its stability. When cells were treated with an Hsp90 inhibitor (geldanamycin or novobiocin), levels of PINK1 were greatly diminished, reflecting its rapid degradation via ubiquitin-proteasome pathway. Similarly, the half-life of a pathogenic PINK1 mutant (L347P) that did not interact with Hsp90 or Cdc37/p50 was only 30 min, whereas that of wild-type PINK1 was 1 h. These results strongly suggest that Hsp90 and Cdc37 are binding partners of PINK1 which regulate its stability.

AB - Mutation of PTEN-induced kinase 1 (PINK1), which encodes a putative mitochondrial serine/threonine kinase, leads to PARK6, an autosomal recessive form of familial Parkinson's disease. Although the precise function(s) of PINK1 protein is unknown, the recessive inheritance of this form of Parkinson's disease suggests loss of PINK1 function is closely associated with its pathogenesis. Here we report that PINK1 forms a complex with the molecular chaperones Hsp90 and Cdc37/p50 within cells, which appears to enhance its stability. When cells were treated with an Hsp90 inhibitor (geldanamycin or novobiocin), levels of PINK1 were greatly diminished, reflecting its rapid degradation via ubiquitin-proteasome pathway. Similarly, the half-life of a pathogenic PINK1 mutant (L347P) that did not interact with Hsp90 or Cdc37/p50 was only 30 min, whereas that of wild-type PINK1 was 1 h. These results strongly suggest that Hsp90 and Cdc37 are binding partners of PINK1 which regulate its stability.

KW - Cdc37

KW - Hsp90

KW - Parkinson's disease

KW - PINK1

KW - Proteasome

KW - Stability

UR - http://www.scopus.com/inward/record.url?scp=41949098617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41949098617&partnerID=8YFLogxK

U2 - 10.1016/j.neures.2008.01.006

DO - 10.1016/j.neures.2008.01.006

M3 - Article

C2 - 18359116

AN - SCOPUS:41949098617

VL - 61

SP - 43

EP - 48

JO - Neuroscience Research

JF - Neuroscience Research

SN - 0168-0102

IS - 1

ER -