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Title: Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)

Journal Article · · Journal of Biological Chemistry
 [1];  [2];  [2];  [1]
  1. Univ. of California, Berkeley, CA (United States)
  2. National Institutes of Health (NIH), Bethesda, MD (United States)

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231; AC02-06CH11357; W-31-109-Eng-38
OSTI ID:
1656465
Journal Information:
Journal of Biological Chemistry, Vol. 289, Issue 8; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 54 works
Citation information provided by
Web of Science

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Cited By (20)

Performance of MDockPP in CAPRI rounds 28-29 and 31-35 including the prediction of water-mediated interactions: Predicting protein-protein interactions in CAPRI journal December 2016
Modeling protein-protein and protein-peptide complexes: CAPRI 6th edition: Modeling Protein-Protein and Protein-Peptide Complexes journal December 2016
FlexPepDock lessons from CAPRI peptide–protein rounds and suggested new criteria for assessment of model quality and utility journal February 2017
Addressing recent docking challenges: A hybrid strategy to integrate template-based and free protein-protein docking: Docking Tool for Predicting Protein-Protein Interactions journal January 2017
Regulation of the divalent metal ion transporter via membrane budding journal June 2016
Targeted protein degradation: expanding the toolbox journal October 2019
The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor journal July 2016
Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity journal July 2019
Versatile communication strategies among tandem WW domain repeats journal February 2015
Adipocyte arrestin domain-containing 3 protein (Arrdc3) regulates uncoupling protein 1 (Ucp1) expression in white adipose independently of canonical changes in β-adrenergic receptor signaling journal March 2017
Structural mechanisms of HECT-type ubiquitin ligases journal January 2018
Differential Phosphorylation Provides a Switch to Control How α-Arrestin Rod1 Down-regulates Mating Pheromone Response in Saccharomyces cerevisiae journal May 2016
Versatile Roles of K63-Linked Ubiquitin Chains in Trafficking journal November 2014
GPCRs in Cancer: Protease-Activated Receptors, Endocytic Adaptors and Signaling journal June 2018
Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms journal September 2019
Correction: Adipocyte arrestin domain-containing 3 protein (Arrdc3) regulates uncoupling protein 1 (Ucp1) expression in white adipose independently of canonical changes in β-adrenergic receptor signaling journal July 2017
Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4 journal October 2019
U24 from Roseolovirus interacts strongly with Nedd4 WW Domains journal January 2017
A hemolytic-uremic syndrome-associated strain O113:H21 Shiga toxin-producing Escherichia coli specifically expresses a transcriptional module containing dicA and is related to gene network dysregulation in Caco-2 cells journal December 2017
Decoding WW domain tandem-mediated target recognitions in tissue growth and cell polarity journal September 2019

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