Structural and functional framework for the autoinhibition of nedd4-family ubiquitin ligases

Sara Mari, Natalia Ruetalo, Elena Maspero, Mira C. Stoffregen, Sebastiano Pasqualato, Simona Polo, Silke Wiesner

Research output: Contribution to journalArticlepeer-review


Nedd4-family ubiquitin ligases are key regulators of cell surface receptor signaling. Their dysregulation is associated with several human diseases, including cancer. Under normal conditions, the activity of various Nedd4 E3s is controlled through an autoinhibitory interaction of the N-terminal C2 domain with the C-terminal catalytic HECT domain. Here, we report the structural and functional framework for this intramolecular interaction. Our nuclear magnetic resonance (NMR) data and biochemical analyses on Smurf2 and Nedd4 show that the C2 domain has the potential to regulate E3 activity by maintaining the HECT domain in a low-activity state where its ability for transthiolation and noncovalent Ub binding are impaired.

Original languageEnglish
Pages (from-to)1639-1649
Number of pages11
Issue number11
Publication statusPublished - Nov 4 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology
  • Medicine(all)


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