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Título: The Parkinson's disease gene, Parkin, ubiquitinates the endocytic accessory protein Eps15 and regulates endocytosis of the epidermal growth factor receptor /
Autores: Bélanger, Catherine.
Fecha: 2006
Publicador: McGill University - MCGILL
Fuente:
Tipo: Electronic Thesis or Dissertation
Tema: Biology, Molecular.
Biology, Neuroscience.
Descripción: Mutations in the parkin gene are responsible for an early-onset autosomal-recessive form of Parkinson's disease. Parkin is an E3 ubiquitin ligase that acts in the covalent attachment of the small protein ubiquitin to substrate proteins. Although many parkin substrates have been identified, none can fully account for the relatively specific death of the dopaminergic neurons in the substantia nigra that occurs in Parkinson's disease. Using an assay that reconstitutes the ubiquitination reaction completely in vitro, I found that not all disease-associated mutations affected parkin's ligase activity. I used this assay to test a potential parkin substrate identified in our lab, the endocytic accessory protein Eps15, which specifically interacts with parkin in a regulated fashion. I found that parkin directly ubiquitinates Eps15 in vitro. Eps15 ubiquitination is known to occur during the process of ligand-induced downregulation of the epidermal growth factor receptor. I found that overexpressing parkin in COS-7 cells inhibited the first step of this process, namely, receptor internalization. These findings add to the knowledge of how pathogenic mutations affect parkin function, and identify a novel role for parkin as a regulator of ligand-induced downregulation of the epidermal growth factor receptor.
Idioma: en