L347P PINK1 mutant that fails to bind to Hsp90/Cdc37 chaperones is rapidly degraded in a proteasome-dependent manner.
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 30min, whereas that of wild-type PINK1 was 1h. These results strongly suggest that Hsp90 and Cdc37 are binding partners of PINK1 which regulate its stability.
Moriwaki
Yasuhiro
Y
Department of Pharmacology, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
Kim
Yeon-Jeong
YJ
Ido
Yukari
Y
Misawa
Hidemi
H
Kawashima
Koichiro
K
Endo
Shogo
S
Takahashi
Ryosuke
R
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018833:Chaperonins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D013058:Mass Spectrometry; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D009675:Novobiocin / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000099202:PTEN-Induced Putative Kinase
D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018833:Chaperonins; D015853:Cysteine Proteinase Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009675:Novobiocin; D011480:Protease Inhibitors; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C498362:CDC37 protein, human; C001277:geldanamycin