Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-related Domain-containing Protein-3 (ARRDC3)
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Crystal structures of ITCH and NEDD4 WW domains in complex with peptide substrates reveal a shallow but hydrophobic binding site that accommodates proline-rich motifs, but with unclear ligandability.
“The crystal structures of ITCH and NEDD4 WW domains in complex with peptide substrates reveal a shallow but hydrophobic binding site that accommodates proline-rich motifs, but with unclear ligandability 125 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [125]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,671 · see citing works
Automated protein model building combined with iterative structure refinement.
Perrakis, A., Morris, R. J., & Lamzin, V. S. (1999) · Nature Structural Biology · doi:10.1038/8263 · Cited by 2,423 · see citing works
Receptor downregulation and multivesicular-body sorting
Katzmann, D. J., Odorizzi, G., & Emr, S. D. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm973 · Cited by 1,201 · see citing works
DESENSITIZATION OF G PROTEIN–COUPLED RECEPTORS AND NEURONAL FUNCTIONS
Gainetdinov, R. R., Premont, R. T., Bohn, L., Lefkowitz, R. J., & Caron, M. G. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144206 · Cited by 864 · see citing works
BALBES: a molecular-replacement pipeline
Long, F., Vagin, A. A., Young, P., & Murshudov, G. N. (2007) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444907050172 · Cited by 717 · see citing works
β-arrestin-mediated receptor trafficking and signal transduction
Shenoy, S. K., & Lefkowitz, R. J. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2011.05.002 · Cited by 714 · see citing works
Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination
Staub, O., Gautschi, I., Ishikawa, T., Breitschopf, K., Ciechanover, A. J., Schild, L., & Rotin, D. (1997) · The EMBO Journal · doi:10.1093/emboj/16.21.6325 · Cited by 697 · see citing works
Sheffield, P., Garrard, S. M., & Derewenda, Z. S. (1999) · Protein Expression and Purification · doi:10.1006/prep.1998.1003 · Cited by 639 · see citing works
The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture
Ingham, R. J., Gish, G. D., & Pawson, T. J. (2004) · Oncogene · doi:10.1038/sj.onc.1207436 · Cited by 531 · see citing works
WW and SH3 domains, two different scaffolds to recognize proline‐rich ligands
Macías, M. J., Wiesner, S., & Sudol, M. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03290-2 · Cited by 488 · see citing works
Lin, C. H., MacGurn, J. A., Chu, T., Stefan, C. J., & Emr, S. D. (2008) · Cell · doi:10.1016/j.cell.2008.09.025 · Cited by 466 · see citing works
Structure of the WW domain of a kinase-associated protein complexed with a proline-rich peptide
Macías, M. J., Hyvönen, M., Baraldi, E., Schultz, J., Sudol, M., Saraste, M., & Oschkinat, H. (1996) · Nature · doi:10.1038/382646a0 · Cited by 424 · see citing works
Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan.
Huang, X. Y., Poy, F., Zhang, R., Joachimiak, A., Sudol, M., & Eck, M. J. (2000) · Nature Structural Biology · doi:10.1038/77923 · Cited by 269 · see citing works
Clathrin‐Dependent Mechanisms of G Protein‐coupled Receptor Endocytosis
Wolfe, B. L., & Trejo, J. (2007) · Traffic · doi:10.1111/j.1600-0854.2007.00551.x · Cited by 242 · see citing works
On the origins of arrestin and rhodopsin
Alvarez, C. E. (2008) · BMC Evolutionary Biology · doi:10.1186/1471-2148-8-222 · Cited by 242 · see citing works
Solution structure of a Nedd4 WW domain-ENaC peptide complex.
Kanelis, V., Rotin, D., & Forman-Kay, J. D. (2001) · Nature Structural Biology · doi:10.1038/87562 · Cited by 220 · see citing works
The ins and outs of G protein-coupled receptor trafficking
Marchese, A., Chen, C., Kim, Y., & Benovic, J. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00134-8 · Cited by 213 · see citing works
Shenoy, S. K., Xiao, K., Venkataramanan, V., Snyder, P. M., Freedman, N. J., & Weissman, A. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709668200 · Cited by 193 · see citing works
Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3
Kamadurai, H. B., Qiu, Y., Deng, A., Harrison, J. S., MacDonald, C., Actis, M., Rodrigues, P., Miller, D. J., Souphron, J., Lewis, S. M., et al. (2013) · eLife · doi:10.7554/elife.00828 · Cited by 165 · see citing works
Nabhan, J. F., Pan, H., & Lu, Q. (2010) · EMBO Reports · doi:10.1038/embor.2010.80 · Cited by 160 · see citing works
The Arrestin Domain-Containing 3 Protein Regulates Body Mass and Energy Expenditure
Patwari, P., Emilsson, V., Schadt, E. E., Chutkow, W. A., Lee, S., Marsili, A., Zhang, Y., Dobrin, R., Cohen, D. E., Larsen, P. R., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.011 · Cited by 119 · see citing works
Han, S., Kommaddi, R. P., & Shenoy, S. K. (2012) · EMBO Reports · doi:10.1038/embor.2012.187 · Cited by 117 · see citing works
Polo, S., Pece, S., & Fiore, P. P. D. (2004) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2004.02.003 · Cited by 107 · see citing works
Fotia, A. B., Dinudom, A., Shearwin, K. E., Koch, J., Korbmacher, C., Cook, D. I., & Kumar, S. (2002) · The FASEB Journal · doi:10.1096/fj.02-0497fje · Cited by 100 · see citing works
Affinity and Specificity of Interactions between Nedd4 Isoforms and the Epithelial Na+ Channel
Henry, P., Kanelis, V., O'Brien, M. C., Kim, B. W., Gautschi, I., Forman-Kay, J. D., Schild, L., & Rotin, D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211153200 · Cited by 91 · see citing works
Structural Determinants for High-Affinity Binding in a Nedd4 WW3∗ Domain-Comm PY Motif Complex
Kanelis, V., Bruce, M. C., Skrynnikov, N. R., Rotin, D., & Forman-Kay, J. D. (2006) · Structure · doi:10.1016/j.str.2005.11.018 · Cited by 90 · see citing works
Molecular Mechanisms of Ubiquitin-Dependent Membrane Traffic
Hurley, J. H., & Stenmark, H. (2011) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-042910-155404 · Cited by 89 · see citing works
Self-citationRole of Ubiquitination in Endocytic Trafficking of G‐Protein‐Coupled Receptors
Hislop, J. N., & von Zastrow, M. (2010) · Traffic · doi:10.1111/j.1600-0854.2010.01121.x · Cited by 87 · see citing works
Shea, F. F., Rowell, J., Li, Y., Chang, T., & Alvarez, C. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050557 · Cited by 68 · see citing works
Lott, J. S., CODDINGTON-LAWSON, S. J., Teesdale‐Spittle, P. H., et al. (2002) · Biochemical Journal · doi:10.1042/0264-6021:3610481 · Cited by 45 · see citing works
Structural Basis for Polyproline Recognition by the FE65 WW Domain
Muthuraman, M., Birrane, G., & Ladias, J. A. A. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.06.064 · Cited by 45 · see citing works
Lott, J. S., CODDINGTON-LAWSON, S. J., Teesdale‐Spittle, P. H., et al. (2002) · Biochemical Journal · doi:10.1042/bj3610481 · Cited by 33 · see citing works
Structure and dynamics of human Nedd4-1 WW3 in complex with the αENaC PY motif
Bobby, R., Medini, K., Neudecker, P., Lee, T. V., Brimble, M. A., McDonald, F. J., Lott, J. S., & Dingley, A. J. (2013) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2013.04.031 · Cited by 31 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
Modeling protein–protein and protein–peptide complexes: CAPRI 6th edition
Lensink, M. F., Velankar, S., & Wodak, S. J. (2017) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25215 · Cited by 222 · see citing works
- Authors
- Qi, S., O'Hayre, M., Gutkind, J. S., & Hurley, J. H.
- Affiliations
- QB3 (US)
- National Institutes of Health (US)
- Corresponding author
- Hurley, James H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 289
- Issue
- 8
- Pages
- 4743-4752
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3931036
- OpenAlex
- W2140210268
- Cited by
- 72
- References
- 37
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 8 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 2
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, W - 31 - 109 - Eng - 38, AC02‐06CH11357, 06CH11357, DE-AC02-)
- American Asthma Foundation
- National Institutes of Health (DE-AC02–06CH11357)
- Office of Science (AC02‐06CH11357, DE-AC02, W-31-109-ENG-38, 06CH11357, DE-AC02-06CH11357)
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Dental and Craniofacial Research
- Basic Energy Sciences (DE-AC02, W-31-109-Eng38, DE-AC- 02-06CH11357, AC02‐06CH11357, 06CH11357)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, W-31-109-ENG-38, 06CH11357)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- ARRDC3, NEDD4, PPxY motif, WW domain, beta2-adrenergic receptor, receptor down-regulation, protein-protein interaction, binding affinity, hydrogen bond network, 310-helix
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Amino Acid Sequence, Calorimetry, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Proline, Protein Binding, Protein Structure, Tertiary, Crystallography, X-Ray, Arrestins, Amino Acid Motifs, Ubiquitin-Protein Ligases, Immunoprecipitation, Mutant Proteins, Endosomal Sorting Complexes Required for Transport, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
