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Mechanism of parkin activation by phosphorylation

A Publisher Correction to this article was published on 19 July 2018

This article has been updated

Abstract

Mutations in the ubiquitin ligase parkin are responsible for a familial form of Parkinson’s disease. Parkin and the PINK1 kinase regulate a quality-control system for mitochondria. PINK1 phosphorylates ubiquitin on the outer membrane of damaged mitochondria, thus leading to recruitment and activation of parkin via phosphorylation of its ubiquitin-like (Ubl) domain. Here, we describe the mechanism of parkin activation by phosphorylation. The crystal structure of phosphorylated Bactrocera dorsalis (oriental fruit fly) parkin in complex with phosphorylated ubiquitin and an E2 ubiquitin-conjugating enzyme reveals that the key activating step is movement of the Ubl domain and release of the catalytic RING2 domain. Hydrogen/deuterium exchange and NMR experiments with the various intermediates in the activation pathway confirm and extend the interpretation of the crystal structure to mammalian parkin. Our results rationalize previously unexplained Parkinson’s disease mutations and the presence of internal linkers that allow large domain movements in parkin.

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Fig. 1: Structure of ternary complex of activated parkin.
Fig. 2: Highlights of the activated parkin structure.
Fig. 3: Loss of the pUbl-binding site prevents parkin activation and pUbl binding.
Fig. 4: HDX–MS detection of conformational changes upon activation of rat parkin by phosphorylation and phospho-ubiquitin binding.
Fig. 5: Pathway of parkin activation.

Change history

  • 19 July 2018

    In the version of this article initially published, RING2 in the schematic to the left in Fig. 1b was mislabeled as RING0. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. M. Pascal (Université de Montréal) for the Staphylococcus aureus sortase A construct and M. Seirafi for preparation of proteins for NMR spectroscopy. We thank the Canadian Light Source for access and data collection on the CMCF beamline 08ID-1, and group members for insightful and helpful discussions. We acknowledge support from the Michael J. Fox Foundation and Canadian Institutes of Health Research.

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Contributions

V.S. designed constructs, froze crystals, performed autoubiquitination assays and prepared HDX samples. V.S. and G.S. performed crystallization and crystal-structure refinement. G.S. performed sortase A reactions. N.S. performed HDX experiments and analysis. G.K., L.M., and N.B. performed NMR experiments. J.-F.T. collected X-ray data, performed phasing and crystal-structure refinement, and analyzed E2-parkin interactions. V.S., G.S., J.-F.T. and K.G. wrote the manuscript. G.L. and K.G. oversaw the project.

Corresponding authors

Correspondence to Jean-François Trempe or Kalle Gehring.

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Integrated supplementary information

Supplementary Figure 1 Sequence alignments of parkin orthologs and E2 enzymes.

a, Sequence alignment of parkin orthologs from Bactrocera dorsalis (BD), Rattus norvegicus (RN) and Homo sapiens (HS). b, Sequence alignment of human E2 ubiquitin-conjugating enzymes. The first five E2 enzymes have been reported to function with parkin in vitro or in cells. Blue shading indicates sequence conservation. Residues in the parkin-UbcH7 interface are labeled in green. Residues in the pUbl-RING0 interface are labeled in red. The catalytic cysteines are labeled in yellow

Supplementary Figure 2 Autoubiquitination assay and crystal structures of phosphorylated Bactrocera parkin fused to UbcH7, in the presence of pUb.

a, The autoubiquitination activity of UbcH7-parkin fusion proteins was tested with phosphorylated proteins in the presence of Ub and visualized on SDS-PAGE gel (n = 1). The first two lanes show the activity of UbcH7 and parkin alone as a control. The third to sixth lanes show the activity of the UbcH7-parkin fusions with different length linkers. The linker length between UbcH7 and parkin is 8, 10, 13, 15 amino acids. b, The structure with the REP linker and RING2 present was solved to 4.8 Å using molecular replacement and zinc SAD. Anomalous map was generated from data collected for UbcH7-phosphorylated parkin/pUb crystal at 1.28 Å wavelength. The anomalous dispersion (light grey mesh) confirms the position of zinc atoms (black spheres) of RING0 (green), RING1 (cyan) and IBR (magenta) in the crystal structure of UbcH7-phosphorylated parkin+pUb. Zinc atoms of symmetry-related UbcH7-phosphorylated parkin+pUb molecules within the crystal are displayed in light orange. No unassigned anomalous density was observed. c, The structure without the disordered elements was solved to 3.8 Å using molecular replacement using 4.8 Å structure as the model. The all-atom root mean square deviation between the two structures is 0.2 Å

Supplementary Figure 3 Steric interactions regulate parkin activity.

a, Overlay of activated Bactrocera parkin structure (colored) with the RING2 modeled from the inactive parkin (grey, PDB 4K95). The C-terminal helix of RING2 occupies the same position as pUbl residues preceding the phosphoserine residue (pSer94). b, Overlay of UbcH7 with the Ubl domain from inactive parkin. The Ubl domain prevents UbcH7 residues Glu60 and Phe63 from binding to residues Gln301, Tyr302, Ser305, and Arg 306 of helix 1 of the parkin RING1 domain. c, Overlay of UbcH7 with the REP linker from inactive parkin. The REP residues preceding the helix block contact of UbcH7 residues Lys96, Pro97, and Ala98 with Bactrocera parkin residues Ala326 and Leu274

Supplementary Figure 4 Electrostatic interactions between UbcH7 and parkin RING1.

a, Structure of Bactrocera parkin bound to UbcH7. An electrostatic potential map was calculated for the isolated RING1 domain. The side-chains of Arg5 and Arg6 in UbcH7 interact with a negatively charged surface in RING1. b, Model of rat Parkin (PDB 4ZYN) bound to UbcH7 with an electrostatic potential map computed for the isolated RING1 domain (REP and Ubl removed)

Supplementary Figure 5 Phosphorylation of parkin mutants for ubiquitin assays.

a, For the autoubiquitination assay, the mutants and WT were phosphorylated and verified on a 7.5% phos-tag SDS-PAGE (n = 1 assay). b, For the complementation assay, the mutants and WT were phosphorylated and verified on a 7.5 % phos-tag SDS-PAGE (n = 1 assay). c, Intact mass spectrometry of the phosphorylated proteins, collected on a Impact II ESI-QTOF (n = 1 assay). The predicted average mass is displayed on the left.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5

Reporting Summary

Supplementary Dataset 1

Uncropped NMR spectra and gel from Figure 3

Supplementary Dataset 2

Graphic presentation of HDX-MS data from Figure 4

Supplementary Dataset 3

Excel data of HDX-MS data from Figure 4

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Sauvé, V., Sung, G., Soya, N. et al. Mechanism of parkin activation by phosphorylation. Nat Struct Mol Biol 25, 623–630 (2018). https://doi.org/10.1038/s41594-018-0088-7

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