A Ubl/ubiquitin switch in the activation of Parkin

• Véronique Sauvé ^[2] ; Asparouh Lilov ^[2] ; Marjan Seirafi ^[2] ; Marta Vranas ^[1] ; Shafqat Rasool ^[1] ; Guennadi Kozlov ^[2] ; Tara Sprules ^[3] ; Jimin Wang ^[4] ; Jean-François Trempe ^[1] ; Kalle Gehring ^[2]
  1. [1] McGill University

     McGill University

     Canadá

     
  2. [2] 1 Groupe de recherché axé sur la structure des protéines and Department of Biochemistry, McGill University Montréal, QC, Canada
  3. [3] 3 Quebec/Eastern Canada High Field NMR Facility (QANUC) Montréal, QC, Canada
  4. [4] 4 Department of Molecular Biophysics and Biochemistry, Yale University New Haven, CT, USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 20, 2015, págs. 2492-2505
• Idioma: inglés
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• Resumen

  • Mutations in Parkin and PINK1 cause an inherited early-onset form of Parkinson's disease. The two proteins function together in a mitochondrial quality control pathway whereby PINK1 accumulates on damaged mitochondria and activates Parkin to induce mitophagy. How PINK1 kinase activity releases the auto-inhibited ubiquitin ligase activity of Parkin remains unclear. Here, we identify a binding switch between phospho-ubiquitin (pUb) and the ubiquitin-like domain (Ubl) of Parkin as a key element. By mutagenesis and SAXS, we show that pUb binds to RING1 of Parkin at a site formed by His302 and Arg305. pUb binding promotes disengagement of the Ubl from RING1 and subsequent Parkin phosphorylation. A crystal structure of Parkin Δ86–130 at 2.54 Å resolution allowed the design of mutations that specifically release the Ubl domain from RING1. These mutations mimic pUb binding and promote Parkin phosphorylation. Measurements of the E2 ubiquitin-conjugating enzyme UbcH7 binding to Parkin and Parkin E3 ligase activity suggest that Parkin phosphorylation regulates E3 ligase activity downstream of pUb binding.