Parkin–phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity

Atul Kumar, Viduth K. Chaugule, Tara E. C. Condos, Kathryn R. Barber, Clare Johnson, Rachel Toth, Ramasubramanian Sundaramoorthy, Axel Knebel, Gary S. Shaw, Helen Walden (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

RING-between-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR ligase is Parkin, mutations in which lead to early-onset hereditary Parkinsonism. Parkin and other RBR ligases share a catalytic RBR module but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during Parkin activation. However, current data on active RBR ligases reflect the absence of regulatory domains. Therefore, it remains unclear how individual RBR ligases are activated, and whether they share a common mechanism. We now report the crystal structure of a human Parkin-phosphoubiquitin complex, which shows that phosphoubiquitin binding induces movement in the 'in-between RING' (IBR) domain to reveal a cryptic ubiquitin-binding site. Mutation of this site negatively affects Parkin's activity. Furthermore, ubiquitin binding promotes cooperation between Parkin molecules, which suggests a role for interdomain association in the RBR ligase mechanism.

Original languageEnglish
Pages (from-to)475-483
Number of pages9
JournalNature Structural & Molecular Biology
Volume24
Issue number5
Early online date17 Apr 2017
DOIs
Publication statusPublished - May 2017

Keywords

  • Enzyme mechanisms
  • Ubiquitin ligases
  • Ubiquitins
  • X-ray crystallography

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