Your browser doesn't support javascript.
loading
Ubiquitin phosphorylated at Ser57 hyper-activates parkin.
George, Susanna; Wang, Sabrina M; Bi, Yumin; Treidlinger, Margot; Barber, Kathryn R; Shaw, Gary S; O'Donoghue, Patrick.
Afiliación
  • George S; Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
  • Wang SM; Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
  • Bi Y; Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
  • Treidlinger M; Department of Chemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
  • Barber KR; Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
  • Shaw GS; Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada; Department of Chemistry, The University of Western Ontario, London, ON N6A 5C1, Canada. Electronic address: gshaw1@uwo.ca.
  • O'Donoghue P; Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada; Department of Chemistry, The University of Western Ontario, London, ON N6A 5C1, Canada. Electronic address: patrick.odonoghue@uwo.ca.
Biochim Biophys Acta Gen Subj ; 1861(11 Pt B): 3038-3046, 2017 Nov.
Article en En | MEDLINE | ID: mdl-28689991
Malfunction of the ubiquitin (Ub) E3 ligase, parkin, leads to defects in mitophagy and protein quality control linked to Parkinson's disease. Parkin activity is stimulated by phosphorylation of Ub at Ser65 (pUbS65). Since the upstream kinase is only known for Ser65 (PINK1), the biochemical function of other phosphorylation sites on Ub remain largely unknown. We used fluorescently labelled and site-specifically phosphorylated Ub substrates to quantitatively relate the position and stoichiometry of Ub phosphorylation to parkin activation. Fluorescence measurements show that pUbS65-stimulated parkin is 5-fold more active than auto-inhibited and un-stimulated parkin, which catalyzes a basal level of auto-ubiquitination. We consistently observed a low but detectable level of parkin activity with pUbS12. Strikingly, pUbS57 hyper-activates parkin, and our data demonstrate that parkin is able to selectively synthesize poly-pUbS57 chains, even when 90% of the Ub in the reaction is un-phosphorylated. We further found that parkin ubiquitinates its physiological substrate Miro-1 with chains solely composed of pUbS65 and more efficiently with pUbS57 chains. Parkin hyper-activation by pUbS57 demonstrates the first PINK1-independent route to active parkin, revealing the roles of multiple ubiquitin phosphorylation sites in governing parkin stimulation and catalytic activity. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Serina / Ubiquitina / Ubiquitina-Proteína Ligasas / Ubiquitinación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Biochim Biophys Acta Gen Subj Año: 2017 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Serina / Ubiquitina / Ubiquitina-Proteína Ligasas / Ubiquitinación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Biochim Biophys Acta Gen Subj Año: 2017 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Países Bajos