High impact information on Nedd4

• It has also been suggested that Comm must be ubiquitinated by the Nedd4 ubiquitin ligase [1].
• Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor [2].
• In tissue culture cells, the dominant-negative form of Nedd4 blocks steady-state Notch internalization and activates Notch signaling independently of ligand binding [3].
• Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation [3].
• We have determined the solution structure and dynamics of a pair of WW domains (WW3-4) from a Drosophila Nedd4 family protein called Suppressor of deltex (Su(dx)), a regulator of Notch receptor signaling [4].

Anatomical context of Nedd4

• Nedd4 family ubiquitin ligases regulate trafficking and degradation of numerous target substrates in different cellular compartments, including at the plasma membrane, in endosomes, in the secretory pathway and in the nucleus [5].

Physical interactions of Nedd4

• RESULTS: We used the Drosophila system to show that Notch is ubiquitinated and destabilized by Nedd4 in a manner requiring the PPSY motif in the Notch intracellular domain [3].
• Here we report the solution structure of the dNedd4 WW3* domain complexed to the second PY motif (227'TGLPSYDEALH237') of Comm. Unexpectedly, there are interactions between WW3* and ligand residues both N- and C-terminal to the PY motif [6].

Other interactions of Nedd4

• This Nedd4 function may be important for protecting unstimulated cells from sporadic activation of Notch signaling [3].
• We show here, however, that ubiquitination of Comm is not required for its function in vitro or in vivo, and that Nedd4 is unlikely to function in axon guidance at the midline [1].

References