Activation of the E3 ubiquitin ligase Parkin

Research output: Contribution to journalArticle

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Abstract

The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependentmitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266-278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025-1026]. Recently resolved partial crystal structures of Parkin showed a 'closed', auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099-2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451-1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser<sup>65</sup> phosphorylation of Parkin is required for its activation and triggering of 'opening' conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cellbased screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488-3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure-function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.

Original languageEnglish (US)
Pages (from-to)269-274
Number of pages6
JournalBiochemical Society Transactions
Volume43
DOIs
StatePublished - Apr 1 2015

Fingerprint

Ubiquitin-Protein Ligases
Ubiquitin
Phosphorylation
Chemical activation
Autophagy
Conformations
Dissection
Molecular modeling
Drug Design
Structural Models
Coenzymes
Molecular Structure
Phosphoric Monoester Hydrolases
Quality Control
Organelles
Computer Simulation
Quality control
Parkinson Disease
Assays
Screening

Keywords

  • Molecular dynamics
  • Parkin
  • Parkinson's disease (PD)
  • Phosphatase and tensin homologue-induced putative kinase 1 (PINK1)
  • Simulations
  • Ubiquitin (Ub)

ASJC Scopus subject areas

  • Biochemistry

Cite this

Activation of the E3 ubiquitin ligase Parkin. / Caulfield, Thomas; Fiesel, Fabienne; Springer, Wolfdieter.

In: Biochemical Society Transactions, Vol. 43, 01.04.2015, p. 269-274.

Research output: Contribution to journalArticle

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