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PDBsum entry 2oo9

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protein Protein-protein interface(s) links
Ligase PDB id
2oo9
Jmol
Contents
Protein chains
46 a.a. *
41 a.a. *
Waters ×73
* Residue conservation analysis
PDB id:
2oo9
Name: Ligase
Title: Crystal structure of the uba domain from human c-cbl ubiquit
Structure: E3 ubiquitin-protein ligase cbl. Chain: a, b, c. Fragment: uba domain. Synonym: signal transduction protein cbl, proto-oncogenE C- casitas b-lineage lymphoma proto-oncogene, ring finger prot engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cbl, cbl2, rnf55. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Resolution:
2.10Å     R-factor:   0.218     R-free:   0.260
Authors: G.Kozlov,K.Gehring
Key ref:
G.Kozlov et al. (2007). Structural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase. J Biol Chem, 282, 27547-27555. PubMed id: 17635922 DOI: 10.1074/jbc.M703333200
Date:
25-Jan-07     Release date:   06-Feb-07    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P22681  (CBL_HUMAN) -  E3 ubiquitin-protein ligase CBL
Seq:
Struc:
 
Seq:
Struc:
906 a.a.
46 a.a.*
Protein chain
Pfam   ArchSchema ?
P22681  (CBL_HUMAN) -  E3 ubiquitin-protein ligase CBL
Seq:
Struc:
 
Seq:
Struc:
906 a.a.
41 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 8 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     regulation of signaling   1 term 
  Biochemical function     ubiquitin-protein ligase activity     1 term  

 

 
DOI no: 10.1074/jbc.M703333200 J Biol Chem 282:27547-27555 (2007)
PubMed id: 17635922  
 
 
Structural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase.
G.Kozlov, P.Peschard, B.Zimmerman, T.Lin, T.Moldoveanu, N.Mansur-Azzam, K.Gehring, M.Park.
 
  ABSTRACT  
 
Ligand-induced down-regulation by the ubiquitin-protein ligases, c-Cbl and Cbl-b, controls signaling downstream from many receptor-tyrosine kinases (RTK). Cbl proteins bind to phosphotyrosine residues on activated RTKs to affect ligand-dependent ubiquitylation of these receptors targeting them for degradation in the lysosome. Both c-Cbl and Cbl-b contain a ubiquitin-associated (UBA) domain, which is important for Cbl dimerization and tyrosine phosphorylation; however, the mechanism of UBA-mediated dimerization and its requirement for Cbl biological activity is unclear. Here, we report the crystal structure of the UBA domain of c-Cbl refined to 2.1-A resolution. The structure reveals the protein is a symmetric dimer tightly packed along a large hydrophobic surface formed by helices 2 and 3. NMR chemical shift mapping reveals heterodimerization can occur with the related Cbl-b UBA domain via the same surface employed for homodimerization. Disruption of c-Cbl dimerization by site-directed mutagenesis impairs c-Cbl phosphorylation following activation of the Met/hepatocyte growth factor RTK and c-Cbl-dependent ubiquitination of Met. This provides direct evidence for a role of Cbl dimerization in terminating signaling following activation of RTKs.
 
  Selected figure(s)  
 
Figure 3.
Structure of the UBA domain from c-Cbl.A, ribbon representation of the UBA dimer. One protomer is shown in magenta, another is in yellow. Helices are labeled as α1-α3 in one protomer and α1′-α3′ in another protomer. B, hydrophobic core of the c-Cbl UBA domain. Respective residues are shown as sticks and labeled. C, the enlarged view of the hydrophobic dimer interface. Key residues in the dimer are shown as sticks and labeled. D, intermolecular hydrogen bonds (dotted line) involving Lys^876 and Glu^894 from both c-Cbl UBA protomers.
Figure 6.
Comparison of protomer arrangement in the structures of (A) c-Cbl UBA domain, (B) Cbl-b UBA domain (PDB code 2OOA), and (C) dimerization domain of doublesex protein (PDB code 1ZV1). Color changes from NH[2] terminus (blue) to COOH terminus (red).
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 27547-27555) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22266821 H.Dou, L.Buetow, A.Hock, G.J.Sibbet, K.H.Vousden, and D.T.Huang (2012).
Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl.
  Nat Struct Mol Biol, 19, 184-192.
PDB codes: 2y1m 2y1n 4a49 4a4b 4a4c
20126411 Y.H.Tan, S.Krishnaswamy, S.Nandi, R.Kanteti, S.Vora, K.Onel, R.Hasina, F.Y.Lo, E.El-Hashani, G.Cervantes, M.Robinson, S.C.Kales, S.Lipkowitz, T.Karrison, M.Sattler, E.E.Vokes, Y.C.Wang, and R.Salgia (2010).
CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases.
  PLoS One, 5, e8972.  
19758803 A.Z.Lai, J.V.Abella, and M.Park (2009).
Crosstalk in Met receptor oncogenesis.
  Trends Cell Biol, 19, 542-551.  
19620964 J.J.Sims, A.Haririnia, B.C.Dickinson, D.Fushman, and R.E.Cohen (2009).
Avid interactions underlie the Lys63-linked polyubiquitin binding specificities observed for UBA domains.
  Nat Struct Mol Biol, 16, 883-889.  
  20368753 M.Sattler, and R.Salgia (2009).
The MET axis as a therapeutic target.
  Update Cancer Ther, 3, 109-118.  
19489725 R.J.Deshaies, and C.A.Joazeiro (2009).
RING domain E3 ubiquitin ligases.
  Annu Rev Biochem, 78, 399-434.  
19489726 Z.Lu, and T.Hunter (2009).
Degradation of activated protein kinases by ubiquitination.
  Annu Rev Biochem, 78, 435-475.  
18596201 Z.R.Zhou, H.C.Gao, C.J.Zhou, Y.G.Chang, J.Hong, A.X.Song, D.H.Lin, and H.Y.Hu (2008).
Differential ubiquitin binding of the UBA domains from human c-Cbl and Cbl-b: NMR structural and biochemical insights.
  Protein Sci, 17, 1805-1814.
PDB codes: 2jnh 2juj
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.