A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease

Donald E. Spratt, R Julio Martinez-Torres, Yeong J. Noh, Pascal Mercier, Noah Manczyk, Kathryn R. Barber, Jacob D. Aguirre, Lynn Burchell, Andrew Purkiss, Helen Walden () and Gary S. Shaw ()
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Donald E. Spratt: Schulich School of Medicine and Dentistry, University of Western Ontario
R Julio Martinez-Torres: Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
Yeong J. Noh: Schulich School of Medicine and Dentistry, University of Western Ontario
Pascal Mercier: Schulich School of Medicine and Dentistry, University of Western Ontario
Noah Manczyk: Schulich School of Medicine and Dentistry, University of Western Ontario
Kathryn R. Barber: Schulich School of Medicine and Dentistry, University of Western Ontario
Jacob D. Aguirre: Schulich School of Medicine and Dentistry, University of Western Ontario
Lynn Burchell: Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
Andrew Purkiss: Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
Helen Walden: Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
Gary S. Shaw: Schulich School of Medicine and Dentistry, University of Western Ontario

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract Mutations in the park2 gene, encoding the RING-inBetweenRING-RING E3 ubiquitin ligase parkin, cause 50% of autosomal recessive juvenile Parkinsonism cases. More than 70 known pathogenic mutations occur throughout parkin, many of which cluster in the inhibitory amino-terminal ubiquitin-like domain, and the carboxy-terminal RING2 domain that is indispensable for ubiquitin transfer. A structural rationale showing how autosomal recessive juvenile Parkinsonism mutations alter parkin function is still lacking. Here we show that the structure of parkin RING2 is distinct from canonical RING E3 ligases and lacks key elements required for E2-conjugating enzyme recruitment. Several pathogenic mutations in RING2 alter the environment of a single surface-exposed catalytic cysteine to inhibit ubiquitination. Native parkin adopts a globular inhibited conformation in solution facilitated by the association of the ubiquitin-like domain with the RING-inBetweenRING-RING C-terminus. Autosomal recessive juvenile Parkinsonism mutations disrupt this conformation. Finally, parkin autoubiquitinates only in cis, providing a molecular explanation for the recessive nature of autosomal recessive juvenile Parkinsonism.

Date: 2013
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DOI: 10.1038/ncomms2983

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