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

摘要

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