4BM9

Structure of the autoinhibited Parkin catalytic domain

Summary for 4BM9

• Entry DOI: 10.2210/pdb4bm9/pdb
• Descriptor: E3 UBIQUITIN-PROTEIN LIGASE PARKIN, ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: ligase, neurodegenerative disease
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm, cytosol: O60260
• Total number of polymer chains: 1
• Total formula weight: 37724.61

Authors

Wauer, T.,Komander, D. (deposition date: 2013-05-07, release date: 2013-06-12, Last modification date: 2024-05-08)

Primary citation

Wauer, T.,Komander, D.
Structure of the Human Parkin Ligase Domain in an Autoinhibited State.
Embo J., 32:2099-, 2013

PubMed 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.

PubMed: 23727886
DOI: 10.1038/EMBOJ.2013.125

Experimental method

X-RAY DIFFRACTION (2.25 Å)