Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming

Elena Maspero, Eleonora Valentini, Sara Mari, Valentina Cecatiello, Paolo Soffientini, Sebastiano Pasqualato, Simona Polo

Research output: Contribution to journalArticlepeer-review

Abstract

Homologous to E6-AP C terminus (HECT) E3 ligases recognize and directly catalyze ligation of ubiquitin (Ub) to their substrates. Molecular details of this process remain unknown. We report the first structure, to our knowledge, of a Ub-loaded E3, the human neural precursor cell-expressed developmentally downregulated protein 4 (Nedd4). The HECT Nedd4 ∼Ub transitory intermediate provides a structural basis for the proposed sequential addition mechanism. The donor Ub, transferred from the E2, is bound to the Nedd4 C lobe with its C-terminal tail locked in an extended conformation, primed for catalysis. We provide evidence that the Nedd4-family members are Lys63-specific enzymes whose catalysis is mediated by an essential C-terminal acidic residue.

Original languageEnglish
Pages (from-to)696-701
Number of pages6
JournalNature Structural and Molecular Biology
Volume20
Issue number6
DOIs
Publication statusPublished - Jun 2013

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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