Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 33, Pages 12022-12027Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802814105
Keywords
parkin; Parkinson's disease; mitochondria; topology
Categories
Funding
- National Institutes of Health [NS42269, NS38370, NS11766, AG21617, A608702, HD83062, ES013177, DK58056]
- U.S. Department of Defense [DAMD 17-03-1]
- Parkinson's Disease Foundation
- Marriott Foundation
- Muscular Dystrophy Association
- Bernard and Anne Spitzer Fund
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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 submitochonchrial 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 IN-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.
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