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PDBsum entry 3buw

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protein ligands Protein-protein interface(s) links
Ligase/signaling protein PDB id
3buw
Jmol
Contents
Protein chains
305 a.a. *
Ligands
SER-PHE-ASN-PRO-
PTR-GLU-PRO-GLU-
LEU
×2
Waters ×575
* Residue conservation analysis
PDB id:
3buw
Name: Ligase/signaling protein
Title: Crystal structure of c-cbl-tkb domain complexed with its binding motif in syk
Structure: 13-meric peptide from tyrosine-protein kinase syk. Chain: a, c. Fragment: unp residues 317-329, ptyr-323 phosphopeptide. Synonym: spleen tyrosine kinase. Engineered: yes. E3 ubiquitin-protein ligase cbl. Chain: b, d. Fragment: c-cbl tkb domain, cbl n-terminal, unp residues
Source: Synthetic: yes. Other_details: synthetic construct. Homo sapiens. Human. Organism_taxid: 9606. Gene: cbl, cbl2, rnf55. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.45Å     R-factor:   0.224     R-free:   0.238
Authors: C.Ng,R.A.Jackson,J.P.Buschdorf,Q.Sun,G.R.Guy,J.Sivaraman
Key ref: C.Ng et al. (2008). Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. EMBO J, 27, 804-816. PubMed id: 18273061 DOI: 10.1038/emboj.2008.18
Date:
03-Jan-08     Release date:   26-Feb-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P22681  (CBL_HUMAN) -  E3 ubiquitin-protein ligase CBL
Seq:
Struc:
 
Seq:
Struc:
906 a.a.
305 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     regulation of signaling   2 terms 
  Biochemical function     signal transducer activity     4 terms  

 

 
DOI no: 10.1038/emboj.2008.18 EMBO J 27:804-816 (2008)
PubMed id: 18273061  
 
 
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.
C.Ng, R.A.Jackson, J.P.Buschdorf, Q.Sun, G.R.Guy, J.Sivaraman.
 
  ABSTRACT  
 
The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.
 

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
21332354 J.H.Hurley, and H.Stenmark (2011).
Molecular mechanisms of ubiquitin-dependent membrane traffic.
  Annu Rev Biophys, 40, 119-142.  
19864419 F.Edwin, K.Anderson, and T.B.Patel (2010).
HECT domain-containing E3 ubiquitin ligase Nedd4 interacts with and ubiquitinates Sprouty2.
  J Biol Chem, 285, 255-264.  
20877636 Q.Sun, R.A.Jackson, C.Ng, G.R.Guy, and J.Sivaraman (2010).
Additional serine/threonine phosphorylation reduces binding affinity but preserves interface topography of substrate proteins to the c-Cbl TKB domain.
  PLoS One, 5, e12819.
PDB codes: 3ob1 3ob2
20213668 R.J.Falconer, A.Penkova, I.Jelesarov, and B.M.Collins (2010).
Survey of the year 2008: applications of isothermal titration calorimetry.
  J Mol Recognit, 23, 395-413.  
19570949 F.Edwin, K.Anderson, C.Ying, and T.B.Patel (2009).
Intermolecular interactions of Sprouty proteins and their implications in development and disease.
  Mol Pharmacol, 76, 679-691.  
19635790 M.Shen, and A.Yen (2009).
c-Cbl tyrosine kinase-binding domain mutant G306E abolishes the interaction of c-Cbl with CD38 and fails to promote retinoic acid-induced cell differentiation and G0 arrest.
  J Biol Chem, 284, 25664-25677.  
19306898 R.L.Geahlen (2009).
Syk and pTyr'd: Signaling through the B cell antigen receptor.
  Biochim Biophys Acta, 1793, 1115-1127.  
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.