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Mol Cell. 2014 Nov 6;56(3):360-75. doi: 10.1016/j.molcel.2014.09.007. Epub 2014 Oct 2.

Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Structural Biology and Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Data and Imaging Analysis Core, Harvard Medical School, Boston, MA 02115, USA.
5
Cell Signaling Technologies, Danvers, MA 01923, USA.
6
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: wade_harper@hms.harvard.edu.

Erratum in

  • Mol Cell. 2014 Nov 6;56(3):462.

Abstract

Phosphorylation is often used to promote protein ubiquitylation, yet we rarely understand quantitatively how ligase activation and ubiquitin (UB) chain assembly are integrated with phosphoregulation. Here we employ quantitative proteomics and live-cell imaging to dissect individual steps in the PINK1 kinase-PARKIN UB ligase mitochondrial control pathway disrupted in Parkinson's disease. PINK1 plays a dual role by phosphorylating PARKIN on its UB-like domain and poly-UB chains on mitochondria. PARKIN activation by PINK1 produces canonical and noncanonical UB chains on mitochondria, and PARKIN-dependent chain assembly is required for accumulation of poly-phospho-UB (poly-p-UB) on mitochondria. In vitro, PINK1 directly activates PARKIN's ability to assemble canonical and noncanonical UB chains and promotes association of PARKIN with both p-UB and poly-p-UB. Our data reveal a feedforward mechanism that explains how PINK1 phosphorylation of both PARKIN and poly-UB chains synthesized by PARKIN drives a program of PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage.

PMID:
25284222
PMCID:
PMC4254048
DOI:
10.1016/j.molcel.2014.09.007
[Indexed for MEDLINE]
Free PMC Article

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