Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)
Copyright policy )Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)
After protracted stimulation, the β2-adrenergic receptor and many other G-protein-coupled receptors are ubiquitinated and down-regulated. Arrestin-related domain-containing protein-3 (ARRDC3) has been proposed to recruit the ubiquitin ligase Nedd4 to the β2-adrenergic receptor. ARRDC3 contains two PPXY motifs that could potentially interact with any of the four WW domains of Nedd4. Here we dissect the interaction determinants. ARRDC3 PPXY-Nedd4 WW dissociation constants vary from unmeasurable to Kd = 3 μM for the third WW domain of Nedd4 binding to the first PPXY motif of ARRDC3. Structures of the uncomplexed and PPXY1-bound WW3 domain were determined at 1.1 and 1.7 Å resolution. The structures revealed conformational changes upon binding and the hydrogen bonding network in exquisite detail. Tight packing of ARRDC3 Val-352', part of a 310 helix at the C terminus of PPXY1, is important for high affinity binding to WW3. Although no single WW domain is strictly essential for the binding of Nedd4 and ARRDC3 expressed in HEK293 cells, high affinity binding of full-length ARRDC3 and Nedd4 is driven by the avid interaction of both PPXY motifs with either the WW2-WW3 or WW3-WW4 combinations, with Kd values as low as 300 nM.
- National Institute of Health Pakistan
- University of California, San Francisco United States
- University of California, Berkeley United States
- QB3 United States
Models, Molecular, 570, Protein Structure, Biochemistry & Molecular Biology, Isothermal Titration Calorimetry, Biomedical and clinical sciences, Proline, Arrestins, Nedd4 Ubiquitin Protein Ligases, Ubiquitin-Protein Ligases, Amino Acid Motifs, Molecular Sequence Data, Calorimetry, Crystallography, X-Ray, Medical and Health Sciences, Models, 2.1 Biological and endogenous factors, Humans, Immunoprecipitation, Amino Acid Sequence, Crystallography, Arrestin, Protein Crystallization, Endosomal Sorting Complexes Required for Transport, Ubiquitin, Molecular, Biological Sciences, Protein Structure, Tertiary, Biological sciences, HEK293 Cells, Chemical sciences, Chemical Sciences, Mutation, X-Ray, Mutant Proteins, Biochemistry and Cell Biology, Ubiquitin Ligase, Tertiary, Protein Binding
Models, Molecular, 570, Protein Structure, Biochemistry & Molecular Biology, Isothermal Titration Calorimetry, Biomedical and clinical sciences, Proline, Arrestins, Nedd4 Ubiquitin Protein Ligases, Ubiquitin-Protein Ligases, Amino Acid Motifs, Molecular Sequence Data, Calorimetry, Crystallography, X-Ray, Medical and Health Sciences, Models, 2.1 Biological and endogenous factors, Humans, Immunoprecipitation, Amino Acid Sequence, Crystallography, Arrestin, Protein Crystallization, Endosomal Sorting Complexes Required for Transport, Ubiquitin, Molecular, Biological Sciences, Protein Structure, Tertiary, Biological sciences, HEK293 Cells, Chemical sciences, Chemical Sciences, Mutation, X-Ray, Mutant Proteins, Biochemistry and Cell Biology, Ubiquitin Ligase, Tertiary, Protein Binding
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