Specificity and Autoregulation of Notch Binding by Tandem WW Domains in Suppressor of Deltex
| Autor: | Martin Baron, Johanna M. Avis, Richard T. Blankley, Alexander P. Golovanov, Martin D. Jennings |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Nedd4 Ubiquitin Protein Ligases Ubiquitin-Protein Ligases Amino Acid Motifs Notch signaling pathway Cooperativity Plasma protein binding Biochemistry Article WW domain Structure-Activity Relationship Protein structure Animals Drosophila Proteins Molecular Biology Genetics Endosomal Sorting Complexes Required for Transport biology Membrane Proteins Cell Biology Endocytosis Recombinant Proteins Protein Structure Tertiary Cell biology Drosophila melanogaster Notch proteins biology.protein Notch binding Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 282:29032-29042 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m703453200 |
| Popis: | WW 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. |
| Databáze: | OpenAIRE |
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