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Mechanism of parkin activation by PINK1

DOI: 10.1038/s41586-018-0224-x DOI Help

Authors: Christina Gladkova (Medical Research Council Laboratory of Molecular Biology) , Sarah Maslen (Medical Research Council Laboratory of Molecular Biology) , J. Mark Skehel (Medical Research Council Laboratory of Molecular Biology) , David Komander (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: June 2018
Diamond Proposal Number(s): 15916

Abstract: Mutations in the E3 ubiquitin ligase parkin (PARK2) and the protein kinase PINK1 (PARK6) are linked to autosomal-recessive juvenile Parkinsonism (AR-JP)1,2, and at the cellular level cause defects in mitophagy, the cellular process that organises destruction of damaged mitochondria3,4. Parkin is autoinhibited, and requires activation by PINK1, which phosphorylates Ser65 in ubiquitin and in the parkin ubiquitin-like (Ubl) domain. Parkin binds phospho-ubiquitin, which enables efficient Parkin phosphorylation; however, the enzyme remains autoinhibited with an inaccessible active site5,6. It is unclear how phosphorylation of parkin activates the molecule. Here we follow the activation of full-length human parkin by hydrogen deuterium exchange mass spectrometry, and reveal large-scale domain rearrangement in the activation process, in which the phospho-Ubl rebinds to the parkin core, and releases the catalytic RING2 domain. A 1.8 Å crystal structure of phosphorylated human parkin reveals the binding site of the phosphorylated Ubl on the unique parkin domain (UPD), involving a phosphate-binding pocket lined by AR-JP mutations. Strikingly, a conserved linker region between Ubl and UPD acts as an activating element (ACT) that contributes to RING2 release by mimicking RING2 interactions on the UPD, explaining further AR-JP mutations. Our data unveil how autoinhibition in parkin is resolved, and suggest how parkin ubiquitinates its substrates via an untethered RING2 domain. This opens exciting new avenues to design parkin activators for clinical use.

Diamond Keywords: Parkinson’s Disease

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 18/06/2018 09:11

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)