Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins

EMBO Rep. 2009 May;10(5):501-7. doi: 10.1038/embor.2009.30. Epub 2009 Apr 3.


HECT domain E3 ubiquitin ligases of the NEDD4 family control many cellular processes, but their regulation is poorly understood. They contain multiple WW domains that recognize PY elements. Here, we show that the small PY-containing membrane proteins, NDFIP1 and NDFIP2 (NEDD4 family-interacting proteins), activate the catalytic activity of ITCH and of several other HECT ligases by binding to them. This releases them from an autoinhibitory intramolecular interaction, which seems to be characteristic of these enzymes. Activation of ITCH requires multiple PY-WW interactions, but little else. Binding of NDFIP proteins is highly dynamic, potentially allowing activated ligases to access other PY-containing substrates. In agreement with this, NDFIP proteins promote ubiquitination in vivo both of Jun proteins, which have a PY motif, and of endophilin, which does not.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Endosomal Sorting Complexes Required for Transport
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Nedd4 Ubiquitin Protein Ligases
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Carrier Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Membrane Proteins
  • NDFIP1 protein, human
  • NDFIP2 protein, human
  • Repressor Proteins
  • ITCH protein, human
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Ubiquitin-Protein Ligases