Autoregulation of Parkin activity through its ubiquitin-like domain

Viduth K Chaugule, Lynn Burchell, Kathryn R Barber, Ateesh Sidhu, Simon J Leslie, Gary S Shaw, Helen Walden (Lead / Corresponding author)

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    204 Citations (Scopus)

    Abstract

    Parkin is an E3-ubiquitin ligase belonging to the RBR (RING-InBetweenRING-RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin-like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C-terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3-ligase activity.

    Original languageEnglish
    Pages (from-to)2853-2867
    Number of pages15
    JournalEMBO Journal
    Volume30
    Issue number14
    DOIs
    Publication statusPublished - 20 Jul 2011

    Keywords

    • CELL-DEATH
    • Parkinson's disease
    • ligase
    • AGGREGATION
    • PINK1
    • ubiquitin
    • RING
    • DISEASE GENE-PRODUCT
    • PROTEIN LIGASE
    • PROTECTIVE FUNCTION
    • COMPLEX
    • INDEPENDENT UBIQUITINATION
    • PATHOGENIC MUTATIONS
    • DEGRADATION

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