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Human Molecular Genetics Advance Access published online on May 19, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl131
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 26, 2006
Revised May 12, 2006
Accepted May 12, 2006

Article

Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity

Cornelia Hampe 1, Hector Ardila-Osorio 1, Margot Fournier 1, Alexis Brice 2 *, and Olga Corti 1 *

1 Neurologie et Thérapeutique Expérimentale, INSERM U679-Université Pierre & Marie Curie, Paris VI, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France
2 Neurologie et Thérapeutique Expérimentale, INSERM U679-Université Pierre & Marie Curie, Paris VI, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France; Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France; Fédération de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France

* To whom correspondence should be addressed.
Alexis Brice, E-mail: brice{at}ccr.jussieu.fr
Olga Corti, E-mail: corti{at}ccr.jussieu.fr


  Abstract

Mutations in the parkin gene, encoding an E3 ubiquitin-protein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. We describe here the biochemical characterization of Parkin and ten pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitin-protein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multiubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.


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