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Structure of the human Parkin ligase domain in an autoinhibited state

Wauer, Tobias, Komander, David·2013·The EMBO Journal
DOI 10.1038/emboj.2013.125PMC PMC3730226
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Abstract

Mutations in the protein Parkin are associated with Parkinson's disease (PD), the second most common neurodegenerative disease in men. Parkin is an E3 ubiquitin (Ub) ligase of the structurally uncharacterized RING‐in‐between‐RING(IBR)‐RING (RBR) family, which, in an HECT‐like fashion, forms a catalytic thioester intermediate with Ub. We here report the crystal structure of human Parkin spanning the Unique Parkin domain (UPD, also annotated as RING0) and RBR domains, revealing a tightly packed structure with unanticipated domain interfaces. The UPD adopts a novel elongated Zn‐binding fold, while RING2 resembles an IBR domain. Two key interactions keep Parkin in an autoinhibited conformation. A linker that connects the IBR with the RING2 over a 50‐Å distance blocks the conserved E2∼Ub binding site of RING1. RING2 forms a hydrophobic interface with the UPD, burying the catalytic Cys431, which is part of a conserved catalytic triad. Opening of intra‐domain interfaces activates Parkin, and enables Ub‐based suicide probes to modify Cys431. The structure further reveals a putative phospho‐peptide docking site in the UPD, and explains many PD‐causing mutations.

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  • Parkin activity is auto-inhibited at baseline.

    “However, parkin activity is auto-inhibited at baseline (Trempe et al, 2013;Wauer & Komander, 2013), and understanding how PINK1-mediated phosphorylation of Ub and parkin triggers its activation and recruitment to mitochondria is incomplete (Kondapalli et al, 2012;Kane et al, 2014;Kazlauskaite et al, 2014;Koyano et al, 2014).”

    From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Wauer & Komander, 2013

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Metadata

Authors
Wauer, T., & Komander, D.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2013-05-31
Volume
32
Issue
15
Pages
2099-2112
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.1038/emboj.2013.125
PMC
PMC3730226
Cited by
328
References
11
Language
en
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