The kinase domain of mitochondrial PINK1 faces the cytoplasm.
Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of autosomal recessive familial Parkinson's disease (PD). Efforts in deducing the PINK1 signaling pathway have been hindered by controversy around its subcellular and submitochondrial localization and the authenticity of its reported substrates. We show here that this mitochondrial protein exhibits a topology in which the kinase domain faces the cytoplasm and the N-terminal tail is inside the mitochondria. Although deletion of the transmembrane domain disrupts this topology, common PD-linked PINK1 mutations do not. These results are critical in rectifying the location and orientation of PINK1 in mitochondria, and they should help decipher its normal physiological function and potential pathogenic role in PD.
Zhou
Chun
C
Department of Neurology, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
Huang
Yong
Y
Shao
Yufang
Y
May
Jessica
J
Prou
Delphine
D
Perier
Celine
C
Dauer
William
W
Schon
Eric A
EA
Przedborski
Serge
S
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000201:enzymology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000201:enzymology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase