PDBsum entry 1yvh

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Ligase,signaling protein,immune system PDB id
Protein chain
304 a.a. *
Waters ×188
* Residue conservation analysis
PDB id:
Name: Ligase,signaling protein,immune system
Title: Crystal structure of thE C-cbl tkb domain in complex with the aps ptyr-618 phosphopeptide
Structure: Cbl e3 ubiquitin protein ligase. Chain: a. Fragment: tyrosine kinase binding domain, residues 25-351. Synonym: signal transduction protein cbl. Proto-oncogenE C- cbl. Casitas b-lineage lymphoma proto- oncogene. Ring finger protein 55. Engineered: yes. 13-mer fragment of sh2 and ph domain-containing adapter protein aps.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cbl, cbl2, rnf55. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: sequence appears in rattus norvegicus, gene aps
Biol. unit: Hexamer (from PQS)
2.05Å     R-factor:   0.209     R-free:   0.247
Authors: J.Hu,S.R.Hubbard
Key ref:
J.Hu and S.R.Hubbard (2005). Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins. J Biol Chem, 280, 18943-18949. PubMed id: 15737992 DOI: 10.1074/jbc.M414157200
15-Feb-05     Release date:   08-Mar-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P22681  (CBL_HUMAN) -  E3 ubiquitin-protein ligase CBL
906 a.a.
304 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: 10.1074/jbc.M414157200 J Biol Chem 280:18943-18949 (2005)
PubMed id: 15737992  
Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins.
J.Hu, S.R.Hubbard.
The Cbl adapter proteins typically function to down-regulate activated protein tyrosine kinases and other signaling proteins by coupling them to the ubiquitination machinery for degradation by the proteasome. Cbl proteins bind to specific tyrosine-phosphorylated sequences in target proteins via the tyrosine kinase-binding (TKB) domain, which comprises a four-helix bundle, an EF-hand calcium-binding domain, and a non-conventional Src homology-2 domain. The previously derived consensus sequence for phosphotyrosine recognition by the Cbl TKB domain is NXpY(S/T)XXP (X denotes lesser residue preference), wherein specificity is conferred primarily by residues C-terminal to the phosphotyrosine. Cbl is recruited to and phosphorylated by the insulin receptor in adipose cells through the adapter protein APS. APS is phosphorylated by the insulin receptor on a C-terminal tyrosine residue, which then serves as a binding site for the Cbl TKB domain. Using x-ray crystallography, site-directed mutagenesis, and calorimetric studies, we have characterized the interaction between the Cbl TKB domain and the Cbl recruitment site in APS, which contains a sequence motif, RA(V/I)XNQpY(S/T), that is conserved in the related adapter proteins SH2-B and Lnk. These studies reveal a novel mode of phosphopeptide interaction with the Cbl TKB domain, in which N-terminal residues distal to the phosphotyrosine directly contact residues of the four-helix bundle of the TKB domain.
  Selected figure(s)  
Figure 2.
FIG. 2. Electron density map in the phosphopeptide-binding site of the c-Cbl TKB domain. The 2F[o] - F[c] electron map density (2.05-Å resolution, 1 contour) is shown as wire mesh (gray) with the refined atomic model superimposed. Residues of the APS phosphopeptide are yellow, residues of the four-helix bundle are green, and residues of the SH2 domain are purple. Ordered water molecules are indicated with red crosses. Residues of the APS phosphopeptide are labeled. The figure was prepared using PYMOL software (
Figure 3.
FIG. 3. Crystal structure of the c-Cbl TKB domain in complex with the APS pTyr-618 phosphopeptide. A, C- trace of the c-Cbl TKB domain with the bound APS phosphopeptide shown in ball-and-stick representation. The four-helix bundle of the TKB domain is colored green, the EF-hand domain is colored orange, and the SH2 domain is colored purple. Carbon atoms of the APS phosphopeptide are colored yellow, oxygen atoms, red, and nitrogen atoms, blue. The Mg2+ ion in the EF-hand domain is represented by a magenta sphere. The N and C termini of the phosphopeptide and the TKB domain are indicated (N and C). B, molecular surface representation of the TKB domain. The surfaces of the four-helix bundle, the EF-hand domain, and the SH2 domain are colored as in A. The APS phosphopeptide is colored yellow, and the superimposed Zap-70 phosphopeptide from the TKB-Zap-70 crystal structure (9) is colored cyan. C, stereo view showing the interactions between the APS phosphopeptide and the c-Cbl TKB domain. Carbon atoms are colored according to domain, as in A. Oxygen atoms are colored red, nitrogen atoms, blue, and sulfur atoms (in the TKB domain), yellow. Water molecules are represented by red spheres. Hydrogen bonds/salt bridges are represented by black dashed lines. The figure was prepared using MOLMOL (A and C) (36) and GRASP (B) (37) software.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 18943-18949) copyright 2005.  
  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
19932172 J.J.Song, M.J.Szczepanski, S.Y.Kim, J.H.Kim, J.Y.An, Y.T.Kwon, M.A.Alcala, D.L.Bartlett, and Y.J.Lee (2010).
c-Cbl-mediated degradation of TRAIL receptors is responsible for the development of the early phase of TRAIL resistance.
  Cell Signal, 22, 553-563.  
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
19680438 C.Werz, K.Köhler, E.Hafen, and H.Stocker (2009).
The Drosophila SH2B family adaptor Lnk acts in parallel to chico in the insulin signaling pathway.
  PLoS Genet, 5, e1000596.  
19926274 P.Filippakopoulos, S.Müller, and S.Knapp (2009).
SH2 domains: modulators of nonreceptor tyrosine kinase activity.
  Curr Opin Struct Biol, 19, 643-649.  
19293402 S.Gery, Q.Cao, S.Gueller, H.Xing, A.Tefferi, and H.P.Koeffler (2009).
Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F.
  J Leukoc Biol, 85, 957-965.  
19001411 S.Hanke, and M.Mann (2009).
The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2.
  Mol Cell Proteomics, 8, 519-534.  
18767163 W.Gan, and B.Roux (2009).
Binding specificity of SH2 domains: insight from free energy simulations.
  Proteins, 74, 996.  
18273061 C.Ng, R.A.Jackson, J.P.Buschdorf, Q.Sun, G.R.Guy, and J.Sivaraman (2008).
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.
  EMBO J, 27, 804-816.
PDB codes: 3bum 3bun 3buo 3buw 3bux
18037921 P.Taylor, E.Blackburn, Y.G.Sheng, S.Harding, K.Y.Hsin, D.Kan, S.Shave, and M.D.Walkinshaw (2008).
Ligand discovery and virtual screening using the program LIDAEUS.
  Br J Pharmacol, 153, S55-S67.  
17102568 K.Kishi, K.Mawatari, K.Sakai-Wakamatsu, T.Yuasa, M.Wang, M.Ogura-Sawa, Y.Nakaya, S.Hatakeyama, and Y.Ebina (2007).
APS-mediated ubiquitination of the insulin receptor enhances its internalization, but does not induce its degradation.
  Endocr J, 54, 77-88.  
17317137 T.Pawson (2007).
Dynamic control of signaling by modular adaptor proteins.
  Curr Opin Cell Biol, 19, 112-116.  
16793553 B.A.Liu, K.Jablonowski, M.Raina, M.Arcé, T.Pawson, and P.D.Nash (2006).
The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling.
  Mol Cell, 22, 851-868.  
16905102 E.Bergamin, J.Wu, and S.R.Hubbard (2006).
Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3.
  Structure, 14, 1285-1292.
PDB code: 2hmh
16741904 G.Swaminathan, and A.Y.Tsygankov (2006).
The Cbl family proteins: ring leaders in regulation of cell signaling.
  J Cell Physiol, 209, 21-43.  
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.