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Autoinhibition And Activation Of Parkin, Jacob D. Aguirre

Electronic Thesis and Dissertation Repository

Mutations in the gene encoding parkin, an E3-ubiquitin ligase, result in 50% of Autosomal Recessive Juvenile Parkinsonism cases. Parkin has been identified as a key mediator of mitochondrial regeneration following oxidative stress, and pathogenic mutations have been shown to impair its ubiquitin ligase activity. Neurodegeneration of dopamine-producing neurons appears to be a downstream consequence of parkin loss-of-function, resulting in early-onset forms of Parkinson’s disease. Although ubiquitination activity is essential for its neuroprotective function, parkin is autoinhibited in its native state by various mechanisms, including its N-terminal ubiquitin-like (UBL) domain. Therefore, the overarching objective of this thesis was to structurally characterize …