PDBsum entry 1b47

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protein metals Protein-protein interface(s) links
Signal transduction PDB id
Protein chains
304 a.a. *
_CA ×3
Waters ×666
* Residue conservation analysis
PDB id:
Name: Signal transduction
Title: Structure of the n-terminal domain of cbl in complex with its binding site in zap-70
Structure: Cbl. Chain: a, b, c. Fragment: n-terminal domain. Synonym: proto-oncogenE C-cbl. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: cytoplasm. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Hexamer (from PQS)
2.20Å     R-factor:   0.218     R-free:   0.266
Authors: W.Meng,S.Sawasdikosol,S.J.Burakoff,M.J.Eck
Key ref:
W.Meng et al. (1999). Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature, 398, 84-90. PubMed id: 10078535 DOI: 10.1038/18050
06-Jan-99     Release date:   27-Apr-99    
Go to PROCHECK summary

Protein chains
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: 10.1038/18050 Nature 398:84-90 (1999)
PubMed id: 10078535  
Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase.
W.Meng, S.Sawasdikosol, S.J.Burakoff, M.J.Eck.
Cbl is an adaptor protein that functions as a negative regulator of many signalling pathways that start from receptors at the cell surface. The evolutionarily conserved amino-terminal region of Cbl (Cbl-N) binds to phosphorylated tyrosine residues and has cell-transforming activity. Point mutations in Cbl that disrupt its recognition of phosphotyrosine also interfere with its negative regulatory function and, in the case of v-cbl, with its oncogenic potential. In T cells, Cbl-N binds to the tyrosine-phosphorylated inhibitory site of the protein tyrosine kinase ZAP-70. Here we describe the crystal structure of Cbl-N, both alone and in complex with a phosphopeptide that represents its binding site in ZAP-70. The structures show that Cbl-N is composed of three interacting domains: a four-helix bundle (4H), an EF-hand calcium-binding domain, and a divergent SH2 domain that was not recognizable from the amino-acid sequence of the protein. The calcium-bound EF hand wedges between the 4H and SH2 domains and roughly determines their relative orientation. In the ligand-occupied structure, the 4H domain packs against the SH2 domain and completes its phosphotyrosine-recognition pocket. Disruption of this binding to ZAP-70 as a result of structure-based mutations in the 4H, EF-hand and SH2 domains confirms that the three domains together form an integrated phosphoprotein-recognition module.
  Selected figure(s)  
Figure 1.
Figure 1: Cbl domain structure and sequence comparisons. a, Ribbon diagram of unliganded Cbl-N. The N-terminal 4H domain is coloured yellow, the EF-hand domain green, and the SH2 domain blue. Secondary-structure elements are labelled A– D in the 4H domain and by established conventions for the EF-hand and SH2 domains. The bound Ca^2+ ion is indicated by a red sphere. Arginine 294 is universally conserved in SH2 domains and participates in phosphotyrosine coordination. b, Diagram of c-Cbl domain structure. The Cbl-N region and adjacent RING finger domain are conserved in all Cbl homologues. The C-terminal region, which contains proline-rich segments and tyrosine phosphorylation sites, is more variable and is completely absent in D-Cbl. A putative leucine zipper has been found near the C terminus of Cbl. c, Aligned sequences of the Cbl-N portion of human c-Cbl, human Cbl-b, Drosophila D-Cbl, and Sli-1. Residues that are identical in at least three of the sequences are shaded yellow. Secondary-structure elements are shown above the sequence and are coloured as in a and b. Black squares indicate residues that coordinate calcium. Red circles mark residues that interact with the bound ZAP-70 peptide. d, Structure-based sequence alignment of Cbl and Lck^23 SH2 domains. Seventy structurally equivalent residues are shaded yellow; -carbons of these seventy residues superimpose with an r.m.s.d. of 1.47 Å. The secondary-structure elements that are present in Lck and other SH2 domains, but not in the Cbl SH2 domain, are indicated by open boxes. e, Superposition of the Cbl SH2 domain (blue) with the Lck SH2 domain (yellow). The structural elements that are absent in the Cbl domain are red.
Figure 3.
Figure 3: Structure of the Cbl-N / ZAP-70 pY292 complex. a, Stereo diagram showing an -carbon trace of the complex. The bound ZAP-70 phosphopeptide is shown in magenta. b, Stereo diagram showing the interactions with the ZAP-70 phosphopeptide. The bound peptide is shown in white. Red spheres represent ordered water molecules that bridge Cbl-N and the bound peptide. Thin blue lines represent hydrogen bonds. In the phosphotyrosine pocket, Tyr 274 in Cbl makes an 'edge-face' interaction with the phosphotyrosine ring, and its hydroxyl group hydrogen-bonds to the carbonyl oxygen of Gly 291 in the ZAP-70 peptide. An arginine residue found in this position in most SH2 domains makes an 'amino–aromatic' interaction with the phosphotyrosine ring and also hydrogen-bonds with the carbonyl of the pY-1 residue of the bound peptide^8. C-terminal to the phosphotyrosine, the proline at position pY+4 in the ZAP-70 peptide binds in a hydrophobic cleft formed by Tyr 307, Phe 336 and Tyr 337, and the glutamic acid residue at pY+3 hydrogen-bonds with the backbone amide of His 320. c, Superposition of the liganded (yellow) and unliganded (blue) Cbl-N structures reveals a shift in the position of the SH2 domain upon phosphopeptide binding. The conformation of the 4H and EF-hand domains is essentially identical in the two structures. In the absence of phosphopeptide, the SH2 domain makes little contact with the 4H domain and its position is likely to vary, as we observe slightly different conformations among the three molecules in the asymmetric unit. Phosphopeptide binding induces a domain 'closure', in which the SH2 domain rotates to pack against the helical domain, completing the phosphotyrosine-binding pocket, as in d. d, Molecular surface representation of the Cbl-N domain, coloured by domain. The 4H domain (yellow) forms a portion of the phosphotyrosine-binding pocket. Residues 289–297 of the bound ZAP-70 phosphopeptide are shown as a stick model. The three N-terminal residues in the peptide are disordered and are not included. In the liganded structure, about 1, 200 Å^2 of the SH2 domain is buried as a result of interaction with the other two domains; 500 Å^2 is buried in the interface with the 4H domain, and 700 Å^2 is buried in the interface with the EF hand. The 4H and EF-hand domains share a solvent-excluding interface of 800 Å^2.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1999, 398, 84-90) copyright 1999.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference Google scholar

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PDB codes: 2y1m 2y1n 4a49 4a4b 4a4c
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Cbl exposes its RING finger.
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PDB codes: 3ob1 3ob2
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PDB codes: 3bum 3bun 3buo 3buw 3bux
18667691 D.Strickland, K.Moffat, and T.R.Sosnick (2008).
Light-activated DNA binding in a designed allosteric protein.
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Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation.
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PDB code: 3bq3
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PDB code: 2izv
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17884340 C.M.Wiggins, H.Band, and S.J.Cook (2007).
c-Cbl is not required for ERK1/2-dependent degradation of BimEL.
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A carboxyl-terminal hydrophobic interface is critical to sodium channel function. Relevance to inherited disorders.
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PDB code: 2ex3
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PDB code: 1yvh
15536084 K.D.Moon, C.B.Post, D.L.Durden, Q.Zhou, P.De, M.L.Harrison, and R.L.Geahlen (2005).
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The genome of the social amoeba Dictyostelium discoideum.
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15923611 T.Brdicka, T.A.Kadlecek, J.P.Roose, A.W.Pastuszak, and A.Weiss (2005).
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  Mol Cell Biol, 25, 4924-4933.  
15465819 Melker, G.van der Horst, and J.Borst (2004).
Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment.
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15208330 A.K.Ghosh, A.L.Reddi, N.L.Rao, L.Duan, V.Band, and H.Band (2004).
Biochemical basis for the requirement of kinase activity for Cbl-dependent ubiquitinylation and degradation of a target tyrosine kinase.
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15117950 C.K.Kassenbrock, and S.M.Anderson (2004).
Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations.
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15345216 L.Duan, A.L.Reddi, A.Ghosh, M.Dimri, and H.Band (2004).
The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling.
  Immunity, 21, 7.  
14974083 M.Halonen, H.Kangas, T.Rüppell, T.Ilmarinen, J.Ollila, M.Kolmer, M.Vihinen, J.Palvimo, J.Saarela, I.Ulmanen, and P.Eskelin (2004).
APECED-causing mutations in AIRE reveal the functional domains of the protein.
  Hum Mutat, 23, 245-257.  
15359630 M.S.Lim, and K.S.Elenitoba-Johnson (2004).
Ubiquitin ligases in malignant lymphoma.
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15123609 P.Peschard, N.Ishiyama, T.Lin, S.Lipkowitz, and M.Park (2004).
A conserved DpYR motif in the juxtamembrane domain of the Met receptor family forms an atypical c-Cbl/Cbl-b tyrosine kinase binding domain binding site required for suppression of oncogenic activation.
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12591907 C.B.Thien, R.M.Scaife, J.M.Papadimitriou, M.A.Murphy, D.D.Bowtell, and W.Y.Langdon (2003).
A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase.
  J Exp Med, 197, 503-513.  
14560016 E.K.Griffiths, O.Sanchez, P.Mill, C.Krawczyk, C.V.Hojilla, E.Rubin, M.M.Nau, R.Khokha, S.Lipkowitz, C.C.Hui, and J.M.Penninger (2003).
Cbl-3-deficient mice exhibit normal epithelial development.
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12941951 H.Wu, D.A.Windmiller, L.Wang, and J.M.Backer (2003).
YXXM motifs in the PDGF-beta receptor serve dual roles as phosphoinositide 3-kinase binding motifs and tyrosine-based endocytic sorting signals.
  J Biol Chem, 278, 40425-40428.  
12842890 J.Liu, S.M.DeYoung, J.B.Hwang, E.E.O'Leary, and A.R.Saltiel (2003).
The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport.
  J Biol Chem, 278, 36754-36762.  
14645539 L.Arnaud, B.A.Ballif, and J.A.Cooper (2003).
Regulation of protein tyrosine kinase signaling by substrate degradation during brain development.
  Mol Cell Biol, 23, 9293-9302.  
  12839496 X.Jiang, and A.Sorkin (2003).
Epidermal growth factor receptor internalization through clathrin-coated pits requires Cbl RING finger and proline-rich domains but not receptor polyubiquitylation.
  Traffic, 4, 529-543.  
12881521 Y.Miura-Shimura, L.Duan, N.L.Rao, A.L.Reddi, H.Shimura, R.Rottapel, B.J.Druker, A.Tsygankov, V.Band, and H.Band (2003).
Cbl-mediated ubiquitinylation and negative regulation of Vav.
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14560012 Y.Yang, P.Villain, T.Mustelin, and C.Couture (2003).
Critical role of Ser-520 phosphorylation for membrane recruitment and activation of the ZAP-70 tyrosine kinase in T cells.
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11777909 B.M.Jehn, I.Dittert, S.Beyer, K.von der Mark, and W.Bielke (2002).
c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1.
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12171941 D.G.Woodside, A.Obergfell, A.Talapatra, D.A.Calderwood, S.J.Shattil, and M.H.Ginsberg (2002).
The N-terminal SH2 domains of Syk and ZAP-70 mediate phosphotyrosine-independent binding to integrin beta cytoplasmic domains.
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12226085 J.R.Courbard, F.Fiore, J.Adélaïde, J.P.Borg, D.Birnbaum, and V.Ollendorff (2002).
Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH.
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Phosphotyrosine-binding domains in signal transduction.
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12024036 M.P.Loreto, D.M.Berry, and C.J.McGlade (2002).
Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor signaling.
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12070286 M.Panigada, S.Porcellini, E.Barbier, S.Hoeflinger, P.A.Cazenave, H.Gu, H.Band, H.von Boehmer, and F.Grassi (2002).
Constitutive endocytosis and degradation of the pre-T cell receptor.
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An essential role of ubiquitination in Cbl-mediated negative regulation of the Src-family kinase Fyn.
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12093870 T.Yasuda, T.Tezuka, A.Maeda, T.Inazu, Y.Yamanashi, H.Gu, T.Kurosaki, and T.Yamamoto (2002).
Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells.
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11828374 V.Di Bartolo, M.Malissen, E.Dufour, E.Sechet, B.Malissen, and O.Acuto (2002).
Tyrosine 315 determines optimal recruitment of ZAP-70 to the T cell antigen receptor.
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11836526 Y.Fujita, G.Krause, M.Scheffner, D.Zechner, H.E.Leddy, J.Behrens, T.Sommer, and W.Birchmeier (2002).
Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex.
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11514605 A.Magnan, V.Di Bartolo, A.M.Mura, C.Boyer, M.Richelme, Y.L.Lin, A.Roure, A.Gillet, C.Arrieumerlou, O.Acuto, B.Malissen, and M.Malissen (2001).
T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase.
  J Exp Med, 194, 491-505.  
11752426 B.Al-Lazikani, F.B.Sheinerman, and B.Honig (2001).
Combining multiple structure and sequence alignments to improve sequence detection and alignment: application to the SH2 domains of Janus kinases.
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11239464 C.B.Thien, F.Walker, and W.Y.Langdon (2001).
RING finger mutations that abolish c-Cbl-directed polyubiquitination and downregulation of the EGF receptor are insufficient for cell transformation.
  Mol Cell, 7, 355-365.  
11316610 C.Krawczyk, and J.M.Penninger (2001).
Molecular controls of antigen receptor clustering and autoimmunity.
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11905825 G.A.Koretzky, and P.S.Myung (2001).
Positive and negative regulation of T-cell activation by adaptor proteins.
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11742985 N.Rao, A.K.Ghosh, S.Ota, P.Zhou, A.L.Reddi, K.Hakezi, B.K.Druker, J.Wu, and H.Band (2001).
The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquitylation upon B-cell receptor stimulation.
  EMBO J, 20, 7085-7095.  
11741535 P.Peschard, T.M.Fournier, L.Lamorte, M.A.Naujokas, H.Band, W.Y.Langdon, and M.Park (2001).
Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein.
  Mol Cell, 8, 995.  
11514606 Q.Gong, X.Jin, A.M.Akk, N.Foger, M.White, G.Gong, J.Bubeck Wardenburg, and A.C.Chan (2001).
Requirement for tyrosine residues 315 and 319 within zeta chain-associated protein 70 for T cell development.
  J Exp Med, 194, 507-518.  
10629042 C.E.Andoniou, N.L.Lill, C.B.Thien, M.L.Lupher, S.Ota, D.D.Bowtell, R.M.Scaife, W.Y.Langdon, and H.Band (2000).
The Cbl proto-oncogene product negatively regulates the Src-family tyrosine kinase Fyn by enhancing its degradation.
  Mol Cell Biol, 20, 851-867.  
  11071924 C.H.Yoon, C.Chang, N.A.Hopper, G.M.Lesa, and P.W.Sternberg (2000).
Requirements of multiple domains of SLI-1, a Caenorhabditis elegans homologue of c-Cbl, and an inhibitory tyrosine in LET-23 in regulating vulval differentiation.
  Mol Biol Cell, 11, 4019-4031.  
10723797 L.A.Norian, and G.A.Koretzky (2000).
Intracellular adapter molecules.
  Semin Immunol, 12, 43-54.  
10781399 L.P.Kane, J.Lin, and A.Weiss (2000).
Signal transduction by the TCR for antigen.
  Curr Opin Immunol, 12, 242-249.  
10679341 L.Shapiro, and T.Harris (2000).
Finding function through structural genomics.
  Curr Opin Biotechnol, 11, 31-35.  
10847681 M.A.Pearson, D.Reczek, A.Bretscher, and P.A.Karplus (2000).
Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain.
  Cell, 101, 259-270.
PDB code: 1ef1
10617627 N.L.Lill, P.Douillard, R.A.Awwad, S.Ota, M.L.Lupher, S.Miyake, N.Meissner-Lula, V.W.Hsu, and H.Band (2000).
The evolutionarily conserved N-terminal region of Cbl is sufficient to enhance down-regulation of the epidermal growth factor receptor.
  J Biol Chem, 275, 367-377.  
10966114 N.Zheng, P.Wang, P.D.Jeffrey, and N.P.Pavletich (2000).
Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases.
  Cell, 102, 533-539.
PDB code: 1fbv
10617633 S.Ota, K.Hazeki, N.Rao, M.L.Lupher, C.E.Andoniou, B.Druker, and H.Band (2000).
The RING finger domain of Cbl is essential for negative regulation of the Syk tyrosine kinase.
  J Biol Chem, 275, 414-422.  
11004605 S.Sawasdikosol, J.C.Pratt, W.Meng, M.J.Eck, and S.J.Burakoff (2000).
Adapting to multiple personalities: Cbl is also a RING finger ubiquitin ligase.
  Biochim Biophys Acta, 1471, M1.  
10647936 T.Hunter (2000).
Signaling--2000 and beyond.
  Cell, 100, 113-127.  
  11029044 T.M.Fournier, L.Lamorte, C.R.Maroun, M.Lupher, H.Band, W.Langdon, and M.Park (2000).
Cbl-transforming variants trigger a cascade of molecular alterations that lead to epithelial mesenchymal conversion.
  Mol Biol Cell, 11, 3397-3410.  
10829062 T.Shishido, T.Akagi, T.Ouchi, M.M.Georgescu, W.Y.Langdon, and H.Hanafusa (2000).
The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation.
  Proc Natl Acad Sci U S A, 97, 6439-6444.  
10684856 T.Yasuda, A.Maeda, M.Kurosaki, T.Tezuka, K.Hironaka, T.Yamamoto, and T.Kurosaki (2000).
Cbl suppresses B cell receptor-mediated phospholipase C (PLC)-gamma2 activation by regulating B cell linker protein-PLC-gamma2 binding.
  J Exp Med, 191, 641-650.  
10669724 X.R.Bustelo (2000).
Regulatory and signaling properties of the Vav family.
  Mol Cell Biol, 20, 1461-1477.  
10635327 G.Levkowitz, H.Waterman, S.A.Ettenberg, M.Katz, A.Y.Tsygankov, I.Alroy, S.Lavi, K.Iwai, Y.Reiss, A.Ciechanover, S.Lipkowitz, and Y.Yarden (1999).
Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.
  Mol Cell, 4, 1029-1040.  
10583414 G.Magistrelli, R.Bosotti, B.Valsasina, C.Visco, R.Perego, S.Toma, O.Acuto, and A.Isacchi (1999).
Role of the Src homology 2 domains and interdomain regions in ZAP-70 phosphorylation and enzymatic activity.
  Eur J Biochem, 266, 1166-1173.  
10354566 H.Miki, and T.Takenawa (1999).
PH domains in WASP - a bug in the system? reply
  Trends Cell Biol, 9, 212.  
10607674 J.D.Forman-Kay, and T.Pawson (1999).
Diversity in protein recognition by PTB domains.
  Curr Opin Struct Biol, 9, 690-695.  
  10490604 J.E.van Leeuwen, P.K.Paik, and L.E.Samelson (1999).
The oncogenic 70Z Cbl mutation blocks the phosphotyrosine binding domain-dependent negative regulation of ZAP-70 by c-Cbl in Jurkat T cells.
  Mol Cell Biol, 19, 6652-6664.  
10449770 J.Tang, S.Sawasdikosol, J.H.Chang, and S.J.Burakoff (1999).
SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling.
  Proc Natl Acad Sci U S A, 96, 9775-9780.  
10591109 K.L.Yap, J.B.Ames, M.B.Swindells, and M.Ikura (1999).
Diversity of conformational states and changes within the EF-hand protein superfamily.
  Proteins, 37, 499-507.  
10347229 S.Miyake, K.P.Mullane-Robinson, N.L.Lill, P.Douillard, and H.Band (1999).
Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation. A critical role for Cbl tyrosine kinase-binding domain.
  J Biol Chem, 274, 16619-16628.  
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.