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Solution structure of the Su(dx) WW4- Notch PY peptide complexSolution structure of the Su(dx) WW4- Notch PY peptide complex
Structural highlights
Function[SUDX_DROME] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Down-regulates Notch/N signaling pathway, probably by promoting Notch ubiquitination, endocytosis and degradation. Involved in wing growth and leg joint formation.[1] [2] [NOTCH_DROME] Signaling protein, which regulates, with both positive and negative signals, the differentiation of at least central and peripheral nervous system and eye, wing disk, oogenesis, segmental appendages such as antennae and legs, and muscles, through lateral inhibition or induction. Functions as a receptor for membrane-bound ligands Delta and Serrate to regulate cell-fate determination. Upon ligand activation, and releasing from the cell membrane, the Notch intracellular domain (NICD) forms a transcriptional activator complex with Su(H) (Suppressor of hairless) and activates genes of the E(spl) complex. Essential for proper differentiation of ectoderm. Fringe (fng) acts in the Golgi to determine the type of O-linked fucose on the EGF modules in N, altering the ability of N to bind with Delta (Dl). O-fut1 also has a role in modulating the interaction. Rumi acts in the endoplasmic reticulum to glucosylate the EGF modules in N, this is required for correct folding and cleavage of N.[3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedWW domains target proline-tyrosine (PY) motifs and frequently function as tandem pairs. When studied in isolation, single WW domains are notably promiscuous and regulatory mechanisms are undoubtedly required to ensure selective interactions. Here, we show that the fourth WW domain (WW4) of Suppressor of Deltex, a modular Nedd4-like protein that down-regulates the Notch receptor, is the primary mediator of a direct interaction with a Notch-PY motif. A natural Trp to Phe substitution in WW4 reduces its affinity for general PY sequences and enhances selective interaction with the Notch-PY motif via compensatory specificity-determining interactions with PY-flanking residues. When WW4 is paired with WW3, domain-domain association, impeding proper folding, competes with Notch-PY binding to WW4. This novel mode of autoinhibition is relieved by binding of another ligand to WW3. Such cooperativity may facilitate the transient regulatory interactions observed in vivo between Su(dx) and Notch in the endocytic pathway. The highly conserved tandem arrangement of WW domains in Nedd4 proteins, and similar arrangements in more diverse proteins, suggests domain-domain communication may be integral to regulation of their associated cellular activities. Specificity and autoregulation of Notch binding by tandem WW domains in suppressor of Deltex.,Jennings MD, Blankley RT, Baron M, Golovanov AP, Avis JM J Biol Chem. 2007 Sep 28;282(39):29032-42. Epub 2007 Jul 26. PMID:17656366[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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