CoChat
Sign Up
Cited by 102

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Dimerisation of the UBA Domain of p62 Inhibits Ubiquitin Binding and Regulates NF-κB Signalling

Long, Jed, Garner, Thomas P., Pandya, Maya J., Craven, C. Jeremy, Chen, Ping, Shaw, Barry, Williamson, Michael P., Layfield, Robert, Searle, Mark S.·2010·Journal of Molecular Biology
DOI 10.1016/j.jmb.2009.11.032
Open this paper in CoChat — free account

Abstract

The ubiquitin (Ub)-binding p62 scaffold protein (encoded by the SQSTM1 gene) regulates a diverse range of signalling pathways leading to activation of the nuclear factor kappa B (NF-kappaB) family of transcription factors and is an important regulator of macroautophagy. Mutations within the gene encoding p62 are commonly found in patients with Paget's disease of bone and largely cluster within the C-terminal ubiquitin-associated (UBA) domain, impairing its ability to bind Ub, resulting in dysregulated NF-kappaB signalling. However, precisely how Ub-binding is regulated at the molecular level is unclear. NMR relaxation dispersion experiments, coupled with concentration-dependent NMR, CD, isothermal titration calorimetry and fluorescence kinetic measurements, reveal that the p62 UBA domain forms a highly stable dimer (K(dim) approximately 4-12 microM at 298 K). NMR analysis shows that the dimer interface partially occludes the Ub-binding surface, particularly at the C-terminus of helix 3, making UBA dimerisation and Ub-binding mutually exclusive processes. Somewhat unusually, the monomeric UBA appears to be the biologically active form and the dimer appears to be the inactive one. Engineered point mutations in loop 1 (E409K and G410K) are shown to destabilise the dimer interface, lead to a higher proportion of the bound monomer and, in NF-kappaB luciferase reporter assays, are associated with reduced NF-kappaB activity compared with wt-p62.

Overview

Integrity signals

Registry

Crossref · 10.1016/j.jmb.2009.11.032

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

Citations

Cites

Show all 2 references

Research works printed but not linked: 54

  1. Moscat, 2007, Signal integration and diversification through the p62 scaffold protein, Trends Biochem. Sci., 32, 95, 10.1016/j.tibs.2006.12.002 · DOI
  2. Moscat, 2009, P62 at the crossroads of autophagy, apoptosis and cancer, Cell, 137, 1001, 10.1016/j.cell.2009.05.023 · DOI · Paper page
  3. Kirkin, 2009, Role for ubiquitin in selective autophagy, Mol. Cell, 34, 259, 10.1016/j.molcel.2009.04.026 · DOI
  4. Bjørkøy, 2005, p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death, J. Cell Biol., 171, 603, 10.1083/jcb.200507002 · DOI · Paper page
  5. Geetha, 2002, Structure and functional properties of the ubiquitin binding protein p62, FEBS Lett., 512, 19, 10.1016/S0014-5793(02)02286-X · DOI
  6. Vadlamudi, 1996, p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins, J. Biol. Chem., 271, 20235, 10.1074/jbc.271.34.20235 · DOI
  7. Ciani, 2003, Structure of the UBA domain of p62(SQSTM1) and implications for mutations which cause Paget's disease of bone, J. Biol. Chem., 278, 37409, 10.1074/jbc.M307416200 · DOI
  8. Durán, 2004, The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis, Dev. Cell, 6, 303, 10.1016/S1534-5807(03)00403-9 · DOI · Paper page
  9. Layfield, 2007, The molecular pathogenesis of Paget disease of bone, Expert Rev. Mol. Med., 9, 1, 10.1017/S1462399407000464 · DOI
  10. Cavey, 2005, Loss of ubiquitin-binding associated with Paget's disease of bone p62 (SQSTM1) mutations, J. Bone Miner. Res., 20, 619, 10.1359/JBMR.041205 · DOI
  11. Layfield, 2007, Ubiquitin-mediated signalling and Paget's disease of bone, BMC Biochem., 8, S5, 10.1186/1471-2091-8-S1-S5 · DOI
  12. Matta-Camacho, 2009, Atypical binding of the Swa2p UBA domain to ubiquitin, J. Mol. Biol., 386, 569, 10.1016/j.jmb.2008.09.086 · DOI
  13. Zhang, 2008, Affinity makes the difference: nonselective interaction of the UBA domain of ubiquilinin-1 with monomeric ubiquitin and polyubiquitin chains, J. Mol. Biol., 377, 162, 10.1016/j.jmb.2007.12.029 · DOI
  14. Kozlov, 2007, Structural basis of ubiquitin recognition by the ubiquitin-associated (UBA) domain of the ubiquitin ligase EDD, J. Biol. Chem., 282, 35787, 10.1074/jbc.M705655200 · DOI
  15. Swanson, 2006, Structural basis for monoubiquitin recognition by the Ede1 UBA domain, J. Mol. Biol., 358, 724, 10.1016/j.jmb.2006.02.059 · DOI
  16. Mueller, 2002, Solution structures of UBA domains reveal a conserved hydrophobic surface for protein–protein interactions, J. Mol. Biol., 319, 1243, 10.1016/S0022-2836(02)00302-9 · DOI
  17. Trempe, 2005, Mechanism of Lys48-linked polyubiquitin chain recognition by the Mud1 UBA domain, EMBO J., 24, 3179, 10.1038/sj.emboj.7600797 · DOI
  18. Kang, 2003, Solution structure of the CUE–ubiquitin complex reveals a conserved mode of ubiquitin binding, Cell, 113, 621, 10.1016/S0092-8674(03)00362-3 · DOI
  19. Varadan, 2005, Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain, Mol. Cell, 18, 687, 10.1016/j.molcel.2005.05.013 · DOI
  20. Ohno, 2005, Structure of the UBA domain of Dsk2p in complex with ubiquitin: molecular determinants for ubiquitin recognition, Structure, 13, 521, 10.1016/j.str.2005.01.011 · DOI
  21. Hurley, 2006, Ubiquitin binding domains, Biochem. J., 399, 361, 10.1042/BJ20061138 · DOI
  22. Hicke, 2005, Ubiquitin-binding domains, Nat. Rev., Mol. Cell Biol., 6, 610, 10.1038/nrm1701 · DOI
  23. Raasi, 2005, Diverse polyubiquitin interaction properties of ubiquitin-associated domains, Nat. Struct. Mol. Biol., 12, 708, 10.1038/nsmb962 · DOI
  24. Prag, 2003, Mechanism of ubiquitin recognition by the CUE domain of Vps9p, Cell, 113, 609, 10.1016/S0092-8674(03)00364-7 · DOI
  25. Kozlov, 2007, Structural basis for UBA-mediated dimerisation of c-Cbl ubiquitin ligase, J. Biol. Chem., 282, 27547, 10.1074/jbc.M703333200 · DOI
  26. Peschard, 2007, Structural basis for ubiquitin-mediated dimerisation and activation of the ubiquitin protein ligase Cbl-b, Mol. Cell, 27, 474, 10.1016/j.molcel.2007.06.023 · DOI
  27. Zhou, 2008, Differential ubiquitin binding of the UBA domains from human c-Cbl and Cbl-b: structural and biochemical insights, Protein Sci., 17, 1805, 10.1110/ps.036384.108 · DOI
  28. Bertolaet, 2001, UBA domains mediate protein–protein interactions between two DNA damage- inducible proteins, J. Mol. Biol., 313, 955, 10.1006/jmbi.2001.5105 · DOI
  29. Walters, 2003, DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a, Proc. Natl Acad. Sci. USA, 100, 12694, 10.1073/pnas.1634989100 · DOI
  30. Long, 2008, Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a novel conformational switch, J. Biol. Chem., 29, 5427, 10.1074/jbc.M704973200 · DOI
  31. Murphy, 2007, Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain, Proc. Natl Acad. Sci. USA, 104, 14336, 10.1073/pnas.0703012104 · DOI
  32. Sugase, 2007, Tailoring relaxation dispersion experiments for fast-associating protein complexes, J. Am. Chem. Soc., 129, 13406, 10.1021/ja0762238 · DOI
  33. Tollinger, 2001, Slow dynamics in folded and unfolded states of an SH3 domain, J. Am. Chem. Soc., 123, 11341, 10.1021/ja011300z · DOI
  34. Jee, 2008, Characterization of specific protein association by 15N CPMG relaxation dispersion NMR: the GB1A34F monomer–dimer equilibrium, J. Phys. Chem. B, 112, 6008, 10.1021/jp076094h · DOI
  35. Korzhnev, 2004, Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR, Nature, 430, 586, 10.1038/nature02655 · DOI
  36. Mittermaier, 2006, New tools provide new insights in NMR studies of protein dynamics, Science, 312, 224, 10.1126/science.1124964 · DOI
  37. Kempf, 2004, Measurement of intermediate exchange phenomena, Methods Mol. Biol., 278, 185
  38. Press, 1992
  39. Hill, 2000, Molecular motions and protein folding: characterization of the backbone dynamics and folding equilibrium of α2D using 13C NMR spin relaxation, J. Am. Chem. Soc., 122, 11610, 10.1021/ja001129b · DOI
  40. Otting, 1989, Extended heteronuclear editing of 2D 1H NMR spectra of isotope-labelled proteins, using the X(ω1,ω2) double half filter, J. Magn. Reson., 85, 586
  41. Rea, 2006, Novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-κB signaling and Paget's disease of bone with a severe phenotype, J. Bone Miner. Res., 21, 1136, 10.1359/jbmr.060405 · DOI
  42. Fenner, 2009, Identification of polyubiquitin binding proteins involved in NF-κB signaling using protein arrays, Biochim. Biophys. Acta, 1794, 1010, 10.1016/j.bbapap.2009.02.013 · DOI
  43. Najat, 2009, Characterization of a non-UBA domain missense mutation of sequestosome 1 (SQSTM1) in Paget's disease of bone, J. Bone Miner. Res., 24, 632, 10.1359/jbmr.081204 · DOI
  44. Marianayagam, 2004, The power of two: protein dimerisation in biology, Trends Biochem. Sci., 29, 618, 10.1016/j.tibs.2004.09.006 · DOI
  45. Murphy, 2007, Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with adjacent kinase domain, Proc. Natl Acad. Sci. USA, 104, 14336, 10.1073/pnas.0703012104 · DOI
  46. Seibenhener, 2007, Sequestome 1/p62—more than just a scaffold, FEBS Lett., 581, 175, 10.1016/j.febslet.2006.12.027 · DOI
  47. Sims, 2009, Avid interactions underlie the Lys63-linked polyubiquitin binding specificities observed for UBA domains, Nat. Struct. Mol. Biol., 16, 883, 10.1038/nsmb.1637 · DOI
  48. Rea, 2009, Sequestosome 1 mutations in Paget's disease of bone in Australia: prevalence, genotype/phenotype correlation, and a novel non-UBA domain mutation (P364S) associated with increased NF-κB signaling without loss of ubiquitin binding, J. Bone Miner. Res., 24, 1216, 10.1359/jbmr.090214 · DOI
  49. Lange, 2005, The kinase domain of titin controls muscle gene expression and protein turnover, Science, 308, 1599, 10.1126/science.1110463 · DOI
  50. Findeisen, 2007, A 1H-NMR thermometer suitable for cryoprobes, Magn. Reson. Chem., 45, 175, 10.1002/mrc.1941 · DOI
  51. Loria, 1999, A relaxation-compensated Carr–Purcell–Meiboom–Gill sequence for characterizing chemical exchange by NMR spectroscopy, J. Am. Chem. Soc., 121, 2331, 10.1021/ja983961a · DOI
  52. Yip, 2005, Improvement of duty-cycle heating compensation in NMR spin relaxation experiments, J. Magn. Reson., 176, 171, 10.1016/j.jmr.2005.06.003 · DOI
  53. Demers, 2009, Binding mechanism of an SH3 domain studied by NMR and ITC, J. Am. Chem. Soc., 131, 4355, 10.1021/ja808255d · DOI
  54. Koradi, 1996, MOLMOL: a program for display and analysis of macromolecular structures, J. Mol. Graphics, 14, 51, 10.1016/0263-7855(96)00009-4 · DOI

Cited by

Sorted by citations

See all 102

Metadata

Authors
Long, J., Garner, T. P., Pandya, M. J., Craven, C. J., Chen, P., Shaw, B., Williamson, M. P., Layfield, R., & Searle, M. S.
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2010-02
Volume
396
Issue
1
Pages
178-194
ISSN
0022-2836
DOI
10.1016/j.jmb.2009.11.032
Cited by
102
References
2
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)

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

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Dimerisation of the UBA Domain of p62 Inhibits Ubiquitin Binding and Regulates NF-κB Signalling. https://app.cochat.ai/papers/10.1016/j.jmb.2009.11.032
The paper
Long, J., Garner, T. P., Pandya, M. J., Craven, C. J., Chen, P., Shaw, B., Williamson, M. P., Layfield, R., & Searle, M. S. (2010). Dimerisation of the UBA Domain of p62 Inhibits Ubiquitin Binding and Regulates NF-κB Signalling. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2009.11.032