PDBsum entry 1a81

Go to PDB code: 
protein Protein-protein interface(s) links
Complex (transferase/peptide) PDB id
Protein chains
254 a.a. *
(+ 0 more) 18 a.a. *
220 a.a. *
* Residue conservation analysis
PDB id:
Name: Complex (transferase/peptide)
Title: Crystal structure of the tandem sh2 domain of the syk kinase a dually tyrosine-phosphorylated itam
Structure: Syk kinase. Chain: a, c, e, g, i, k. Fragment: tandem sh2 domain. Engineered: yes. T-cell surface glycoprotein cd3 epsilon chain. Chain: b, d, f, h, j, l. Synonym: itam peptide. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: escherichia coli. Expression_system_taxid: 562. Organism_taxid: 9606
Biol. unit: Hexamer (from PQS)
3.00Å     R-factor:   0.226     R-free:   0.317
Authors: K.Fuetterer,G.Waksman
Key ref:
K.Fütterer et al. (1998). Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide. J Mol Biol, 281, 523-537. PubMed id: 9698567 DOI: 10.1006/jmbi.1998.1964
31-Mar-98     Release date:   21-Oct-98    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK
635 a.a.
254 a.a.
Protein chains
Pfam   ArchSchema ?
P07766  (CD3E_HUMAN) -  T-cell surface glycoprotein CD3 epsilon chain
207 a.a.
18 a.a.
Protein chains
Pfam   ArchSchema ?
P43405  (KSYK_HUMAN) -  Tyrosine-protein kinase SYK
635 a.a.
220 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, C, E, G, I, K: E.C.  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     cell surface receptor signaling pathway   1 term 
  Biochemical function     transmembrane signaling receptor activity     2 terms  


DOI no: 10.1006/jmbi.1998.1964 J Mol Biol 281:523-537 (1998)
PubMed id: 9698567  
Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide.
K.Fütterer, J.Wong, R.A.Grucza, A.C.Chan, G.Waksman.
The Syk family of kinases, consisting of ZAP-70 and Syk, play essential roles in a variety of immune and non-immune cells. This family of kinases is characterized by the presence of two adjacent SH2 domains which mediate their localization to the membrane through receptor encoded tyrosine phosphorylated motifs. While these two kinases share many structural and functional features, the more ubiquitous nature of Syk has suggested that this kinase may accommodate a greater variety of motifs to mediate its function. We present the crystal structure of the tandem SH2 domain of Syk complexed with a dually phosphorylated ITAM peptide. The structure was solved by multiple isomorphous replacement at 3.0 A resolution. The asymmetric unit comprises six copies of the liganded protein, revealing a surprising flexibility in the relative orientation of the two SH2 domains. The C-terminal phosphotyrosine-binding site is very different from the equivalent region of ZAP-70, suggesting that in contrast to ZAP-70, the two SH2 domains of Syk can function as independent units. The conformational flexibility and structural independence of the SH2 modules of Syk likely provides the molecular basis for the more ubiquitous involvement of Syk in a variety of signal transduction pathways.
  Selected figure(s)  
Figure 1.
Figure 1. Representative regions of the averaged exper- imental electron density contoured at 1.2s. A, The region encompasses the C-terminal phosphotyrosine- binding site and shows continuous and unambiguous electron density for all elements of the phosphotyrosine- binding site of Syk-N. Helix aA, the peptide's C-term- inal phosphotyrosine (pYc), as well as residues Arg-bB5, Arg-aA2, His-bD3, and His-bD4 in Syk-N are indicated. B, Same region as in A, rotated by 90° about the axis of the aA helix, illustrating the proximity of Syk-C. Resi- dues in the C and N-terminal SH2 domains are distin- guished by prefixes C- and N-, respectively. Clear density is observed for the elements of the phosphotyro- sine-binding site contributed by Syk-N, while Lys-bF1, the only residue of Syk-C participating in the coordi- nation of the phosphotyrosine, is poorly defined. Unam- biguous density for this side-chain was only observed in omit maps and in only three of the six molecules. The Figure was generated using the program O (Jones et al., 1991).
  The above figure is reprinted by permission from Elsevier: J Mol Biol (1998, 281, 523-537) copyright 1998.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20467426 A.Mócsai, J.Ruland, and V.L.Tybulewicz (2010).
The SYK tyrosine kinase: a crucial player in diverse biological functions.
  Nat Rev Immunol, 10, 387-402.  
20940318 B.Heizmann, M.Reth, and S.Infantino (2010).
Syk is a dual-specificity kinase that self-regulates the signal output from the B-cell antigen receptor.
  Proc Natl Acad Sci U S A, 107, 18563-18568.  
20001666 D.Ghosh, and G.C.Tsokos (2010).
Spleen tyrosine kinase: an Src family of non-receptor kinase has multiple functions and represents a valuable therapeutic target in the treatment of autoimmune and inflammatory diseases.
  Autoimmunity, 43, 48-55.  
  20452964 H.Wang, T.A.Kadlecek, B.B.Au-Yeung, H.E.Goodfellow, L.Y.Hsu, T.S.Freedman, and A.Weiss (2010).
ZAP-70: an essential kinase in T-cell signaling.
  Cold Spring Harb Perspect Biol, 2, a002279.  
19959716 J.Smith, J.P.McDaid, G.Bhangal, R.Chawanasuntorapoj, E.S.Masuda, H.T.Cook, C.D.Pusey, and F.W.Tam (2010).
A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis.
  J Am Soc Nephrol, 21, 231-236.  
20335218 M.Buchner, C.Baer, G.Prinz, C.Dierks, M.Burger, T.Zenz, S.Stilgenbauer, H.Jumaa, H.Veelken, and K.Zirlik (2010).
Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia.
  Blood, 115, 4497-4506.  
20727029 M.Werner, E.Hobeika, and H.Jumaa (2010).
Role of PI3K in the generation and survival of B cells.
  Immunol Rev, 237, 55-71.  
19409513 E.Arias-Palomo, M.A.Recuero-Checa, X.R.Bustelo, and O.Llorca (2009).
Conformational rearrangements upon Syk auto-phosphorylation.
  Biochim Biophys Acta, 1794, 1211-1217.  
19763316 J.Kuil, H.M.Branderhorst, R.J.Pieters, Mol, and R.M.Liskamp (2009).
ITAM-derived phosphopeptide-containing dendrimers as multivalent ligands for Syk tandem SH2 domain.
  Org Biomol Chem, 7, 4088-4094.  
19714714 J.Kuil, L.T.van Wandelen, Mol, and R.M.Liskamp (2009).
Switching between low and high affinity for the Syk tandem SH2 domain by irradiation of azobenzene containing ITAM peptidomimetics.
  J Pept Sci, 15, 685-691.  
19306898 R.L.Geahlen (2009).
Syk and pTyr'd: Signaling through the B cell antigen receptor.
  Biochim Biophys Acta, 1793, 1115-1127.  
19391622 S.H.Bae, H.J.Dyson, and P.E.Wright (2009).
Prediction of the rotational tumbling time for proteins with disordered segments.
  J Am Chem Soc, 131, 6814-6821.  
19240758 S.Herzog, M.Reth, and H.Jumaa (2009).
Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling.
  Nat Rev Immunol, 9, 195-205.  
18818202 E.Tsang, A.M.Giannetti, D.Shaw, M.Dinh, J.K.Tse, S.Gandhi, H.Ho, S.Wang, E.Papp, and J.M.Bradshaw (2008).
Molecular mechanism of the syk activation switch.
  J Biol Chem, 283, 32650-32659.  
17921498 H.Kono, T.Yuasa, S.Nishiue, and K.Yura (2008).
coliSNP database server mapping nsSNPs on protein structures.
  Nucleic Acids Res, 36, D409-D413.  
18689684 Y.Zhang, H.Oh, R.A.Burton, J.W.Burgner, R.L.Geahlen, and C.B.Post (2008).
Tyr130 phosphorylation triggers Syk release from antigen receptor by long-distance conformational uncoupling.
  Proc Natl Acad Sci U S A, 105, 11760-11765.  
18021750 E.Arias-Palomo, M.A.Recuero-Checa, X.R.Bustelo, and O.Llorca (2007).
3D structure of Syk kinase determined by single-particle electron microscopy.
  Biochim Biophys Acta, 1774, 1493-1499.  
17679556 H.M.Lee, H.J.Kim, H.J.Park, K.J.Won, J.Kim, H.S.Shin, P.J.Park, H.J.Kim, K.Y.Lee, S.H.Park, C.K.Lee, and B.Kim (2007).
Spleen tyrosine kinase participates in Src-mediated migration and proliferation by PDGF-BB in rat aortic smooth muscle cells.
  Arch Pharm Res, 30, 761-769.  
17506820 H.Sarantis, and S.D.Gray-Owen (2007).
The specific innate immune receptor CEACAM3 triggers neutrophil bactericidal activities via a Syk kinase-dependent pathway.
  Cell Microbiol, 9, 2167-2180.  
17656366 M.D.Jennings, R.T.Blankley, M.Baron, A.P.Golovanov, and J.M.Avis (2007).
Specificity and autoregulation of Notch binding by tandem WW domains in suppressor of Deltex.
  J Biol Chem, 282, 29032-29042.
PDB code: 2jmf
17624955 S.M.Grande, G.Bannish, E.M.Fuentes-Panana, E.Katz, and J.G.Monroe (2007).
Tonic B-cell and viral ITAM signaling: context is everything.
  Immunol Rev, 218, 214-234.  
17353363 W.Zou, H.Kitaura, J.Reeve, F.Long, V.L.Tybulewicz, S.J.Shattil, M.H.Ginsberg, F.P.Ross, and S.L.Teitelbaum (2007).
Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.
  J Cell Biol, 176, 877-888.  
16557260 J.G.Monroe (2006).
ITAM-mediated tonic signalling through pre-BCR and BCR complexes.
  Nat Rev Immunol, 6, 283-294.  
16861349 J.H.Lee, Y.M.Kim, N.W.Kim, J.W.Kim, E.Her, B.K.Kim, J.H.Kim, S.H.Ryu, J.W.Park, D.W.Seo, J.W.Han, M.A.Beaven, and W.S.Choi (2006).
Phospholipase D2 acts as an essential adaptor protein in the activation of Syk in antigen-stimulated mast cells.
  Blood, 108, 956-964.  
16431925 J.Lu, W.H.Lin, S.Y.Chen, R.Longnecker, S.C.Tsai, C.L.Chen, and C.H.Tsai (2006).
Syk tyrosine kinase mediates Epstein-Barr virus latent membrane protein 2A-induced cell migration in epithelial cells.
  J Biol Chem, 281, 8806-8814.  
16563097 S.M.Grande, S.R.Ross, and J.G.Monroe (2006).
Viral immunoreceptor-associated tyrosine-based activation motifs: potential players in oncogenesis.
  Future Oncol, 2, 301-310.  
15842733 A.Elkak, W.Al Sarakbi, and K.Mokbel (2005).
SYK expression in human breast cancer.
  J Carcinog, 4, 7.  
15797511 G.Berton, A.Mócsai, and C.A.Lowell (2005).
Src and Syk kinases: key regulators of phagocytic cell activation.
  Trends Immunol, 26, 208-214.  
15800671 J.C.Nolz, R.C.Tschumper, B.T.Pittner, J.R.Darce, N.E.Kay, and D.F.Jelinek (2005).
ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype.
  Leukemia, 19, 1018-1024.  
15914019 M.I.Catalina, M.J.Fischer, F.J.Dekker, R.M.Liskamp, and A.J.Heck (2005).
Binding of a diphosphorylated-ITAM peptide to spleen tyrosine kinase (Syk) induces distal conformational changes: a hydrogen exchange mass spectrometry study.
  J Am Soc Mass Spectrom, 16, 1039-1051.  
16185147 M.Ulanova, F.Duta, L.Puttagunta, A.D.Schreiber, and A.D.Befus (2005).
Spleen tyrosine kinase (Syk) as a novel target for allergic asthma and rhinitis.
  Expert Opin Ther Targets, 9, 901-921.  
16252296 Mol, M.I.Catalina, F.J.Dekker, M.J.Fischer, A.J.Heck, and R.M.Liskamp (2005).
Protein flexibility and ligand rigidity: a thermodynamic and kinetic study of ITAM-based ligand binding to Syk tandem SH2.
  Chembiochem, 6, 2261-2270.  
16200067 P.Tolar, H.W.Sohn, and S.K.Pierce (2005).
The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer.
  Nat Immunol, 6, 1168-1176.  
15056653 E.Hong, J.Shin, H.I.Kim, S.T.Lee, and W.Lee (2004).
Solution structure and backbone dynamics of the non-receptor protein-tyrosine kinase-6 Src homology 2 domain.
  J Biol Chem, 279, 29700-29708.
PDB code: 1rja
14962183 K.A.Pike, E.Baig, and M.J.Ratcliffe (2004).
The avian B-cell receptor complex: distinct roles of Igalpha and Igbeta in B-cell development.
  Immunol Rev, 197, 10-25.  
14672952 M.S.Sozio, M.A.Mathis, J.A.Young, S.Wälchli, L.A.Pitcher, P.C.Wrage, B.Bartók, A.Campbell, J.D.Watts, R.Aebersold, R.H.Van Huijsduijnen, and N.S.van Oers (2004).
PTPH1 is a predominant protein-tyrosine phosphatase capable of interacting with and dephosphorylating the T cell receptor zeta subunit.
  J Biol Chem, 279, 7760-7769.  
14517908 A.Nayeem, S.Krystek, and T.Stouch (2003).
An assessment of protein-ligand binding site polarizability.
  Biopolymers, 70, 201-211.  
12551896 E.G.Stein, R.Ghirlando, and S.R.Hubbard (2003).
Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity.
  J Biol Chem, 278, 13257-13264.
PDB code: 1nrv
12614351 L.A.Pitcher, J.A.Young, M.A.Mathis, P.C.Wrage, B.Bartók, and N.S.van Oers (2003).
The formation and functions of the 21- and 23-kDa tyrosine-phosphorylated TCR zeta subunits.
  Immunol Rev, 191, 47-61.  
14552840 L.A.Pitcher, and N.S.van Oers (2003).
T-cell receptor signal transmission: who gives an ITAM?
  Trends Immunol, 24, 554-560.  
14657388 S.Kumaran, R.A.Grucza, and G.Waksman (2003).
The tandem Src homology 2 domain of the Syk kinase: a molecular device that adapts to interphosphotyrosine distances.
  Proc Natl Acad Sci U S A, 100, 14828-14833.  
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.
  J Biol Chem, 277, 39401-39408.  
12417718 J.Zhang, E.Berenstein, and R.P.Siraganian (2002).
Phosphorylation of Tyr342 in the linker region of Syk is critical for Fc epsilon RI signaling in mast cells.
  Mol Cell Biol, 22, 8144-8154.  
11994738 M.B.Yaffe (2002).
Phosphotyrosine-binding domains in signal transduction.
  Nat Rev Mol Cell Biol, 3, 177-186.  
11847104 O.Billker, A.Popp, V.Brinkmann, G.Wenig, J.Schneider, E.Caron, and T.F.Meyer (2002).
Distinct mechanisms of internalization of Neisseria gonorrhoeae by members of the CEACAM receptor family involving Rac1- and Cdc42-dependent and -independent pathways.
  EMBO J, 21, 560-571.  
12453414 V.Rolli, M.Gallwitz, T.Wossning, A.Flemming, W.W.Schamel, C.Zürn, and M.Reth (2002).
Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop.
  Mol Cell, 10, 1057-1069.  
  11913945 J.Wienands, and N.Engels (2001).
Multitasking of Ig-alpha and Ig-beta to regulate B cell antigen receptor function.
  Int Rev Immunol, 20, 679-696.  
11449366 N.Engels, B.Wollscheid, and J.Wienands (2001).
Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha.
  Eur J Immunol, 31, 2126-2134.  
11828442 R.Ruijtenbeek, J.A.Kruijtzer, W.van de Wiel, M.J.Fischer, M.Flück, F.A.Redegeld, R.M.Liskamp, and F.P.Nijkamp (2001).
Peptoid - peptide hybrids that bind Syk SH2 domains involved in signal transduction.
  Chembiochem, 2, 171-179.  
11406361 S.Latour, and A.Veillette (2001).
Proximal protein tyrosine kinases in immunoreceptor signaling.
  Curr Opin Immunol, 13, 299-306.  
11046148 G.Winberg, L.Matskova, F.Chen, P.Plant, D.Rotin, G.Gish, R.Ingham, I.Ernberg, and T.Pawson (2000).
Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases.
  Mol Cell Biol, 20, 8526-8535.  
11085181 H.Jacobs (2000).
TCR-independent T cell development mediated by gain-of-oncogene function or loss-of-tumor-suppressor gene function.
  Semin Immunol, 12, 487-502.  
10900006 R.Müller, J.Wienands, and M.Reth (2000).
The serine and threonine residues in the Ig-alpha cytoplasmic tail negatively regulate immunoreceptor tyrosine-based activation motif-mediated signal transduction.
  Proc Natl Acad Sci U S A, 97, 8451-8454.  
  10752619 R.O'Brien, P.Rugman, D.Renzoni, M.Layton, R.Handa, K.Hilyard, M.D.Waterfield, P.C.Driscoll, and J.E.Ladbury (2000).
Alternative modes of binding of proteins with tandem SH2 domains.
  Protein Sci, 9, 570-579.  
11123912 T.Weber, B.Schaffhausen, Y.Liu, and U.L.Günther (2000).
NMR structure of the N-SH2 of the p85 subunit of phosphoinositide 3-kinase complexed to a doubly phosphorylated peptide reveals a second phosphotyrosine binding site.
  Biochemistry, 39, 15860-15869.
PDB codes: 1fu5 1fu6
11232302 M.Reth, and J.Wienands (1999).
The maintenance and the activation signal of the B-cell antigen receptor.
  Cold Spring Harb Symp Quant Biol, 64, 323-328.  
10438475 P.G.Swann, S.Odom, Y.J.Zhou, Z.Szallasi, P.M.Blumberg, P.Draber, and J.Rivera (1999).
Requirement for a negative charge at threonine 60 of the FcRgamma for complete activation of Syk.
  J Biol Chem, 274, 23068-23077.  
10398925 R.A.Grucza, J.M.Bradshaw, K.Fütterer, and G.Waksman (1999).
SH2 domains: from structure to energetics, a dual approach to the study of structure-function relationships.
  Med Res Rev, 19, 273-293.  
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 code is shown on the right.