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PDBsum entry 2knv

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protein Protein-protein interface(s) links
Protein binding PDB id
2knv
Jmol
Contents
Protein chain
52 a.a. *
* Residue conservation analysis
PDB id:
2knv
Name: Protein binding
Title: Nmr dimer structure of the uba domain of p62 (sqstm1)
Structure: Sequestosome-1. Chain: a, b. Fragment: uba domain, unp residues 387-436. Synonym: phosphotyrosine-independent ligand for the lck sh2 domain of 62 kda, ubiquitin-binding protein p62, ebi3- associated protein of 60 kda, p60, ebiap. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sqstm1. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_variant: (de3).
NMR struc: 10 models
Authors: J.E.Long,M.S.Searle
Key ref: J.Long et al. (2010). Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling. J Mol Biol, 396, 178-194. PubMed id: 19931284 DOI: 10.1016/j.jmb.2009.11.032
Date:
04-Sep-09     Release date:   15-Dec-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q13501  (SQSTM_HUMAN) -  Sequestosome-1
Seq:
Struc:
440 a.a.
52 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 

 
DOI no: 10.1016/j.jmb.2009.11.032 J Mol Biol 396:178-194 (2010)
PubMed id: 19931284  
 
 
Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling.
J.Long, T.P.Garner, M.J.Pandya, C.J.Craven, P.Chen, B.Shaw, M.P.Williamson, R.Layfield, M.S.Searle.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20616007 C.A.Whitehouse, S.Waters, K.Marchbank, A.Horner, N.W.McGowan, J.V.Jovanovic, G.M.Xavier, T.G.Kashima, M.T.Cobourne, G.O.Richards, P.T.Sharpe, T.M.Skerry, A.E.Grigoriadis, and E.Solomon (2010).
Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity.
  Proc Natl Acad Sci U S A, 107, 12913-12918.  
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