General Information

Database Accession: DI1000129

Name: Tandem SH2 domain of the Syk tyrosine kinase bound to a dually phosphorylated ITAM peptide from T-cell surface glycoprotein CD3 epsilon chain

PDB ID: 1a81 PDB

Experimental method: X-ray (3.00 Å)

Source organism: Homo sapiens

Proof of disorder: Confirmed

Primary publication of the structure:

Fütterer K, Wong J, Grucza RA, Chan AC, Waksman G
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.
(1998) J. Mol. Biol. 281: 523-37

PMID: 9698567 PubMed

Abstract:

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.

Function and Biology Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown.

Molecular function:

protein kinase binding Interacting selectively and non-covalently with a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate. GeneOntology

signal transducer activity, downstream of receptor Conveys a signal from an upstream receptor or intracellular signal transducer, converting the signal into a form where it can ultimately trigger a change in the state or activity of a cell. GeneOntology

receptor binding Interacting selectively and non-covalently with one or more specific sites on a receptor molecule, a macromolecule that undergoes combination with a hormone, neurotransmitter, drug or intracellular messenger to initiate a change in cell function. GeneOntology

protein domain specific binding Interacting selectively and non-covalently with a specific domain of a protein. GeneOntology

Biological process:

transmembrane receptor protein tyrosine kinase signaling pathway A series of molecular signals initiated by the binding of an extracellular ligand to a receptor on the surface of the target cell where the receptor possesses tyrosine kinase activity, and ending with regulation of a downstream cellular process, e.g. transcription. GeneOntology

positive regulation of alpha-beta T cell proliferation Any process that activates or increases the frequency, rate or extent of alpha-beta T cell proliferation. GeneOntology

positive regulation of peptidyl-tyrosine phosphorylation Any process that activates or increases the frequency, rate or extent of the phosphorylation of peptidyl-tyrosine. GeneOntology

positive regulation of calcium-mediated signaling Any process that activates or increases the frequency, rate or extent of calcium-mediated signaling. GeneOntology

positive regulation of immune response Any process that activates or increases the frequency, rate or extent of the immune response, the immunological reaction of an organism to an immunogenic stimulus. GeneOntology

response to external stimulus Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an external stimulus. GeneOntology

positive regulation of cytokine production Any process that activates or increases the frequency, rate or extent of production of a cytokine. GeneOntology

leukocyte differentiation The process in which a relatively unspecialized hemopoietic precursor cell acquires the specialized features of a leukocyte. A leukocyte is an achromatic cell of the myeloid or lymphoid lineages capable of ameboid movement, found in blood or other tissue. GeneOntology

T cell activation The change in morphology and behavior of a mature or immature T cell resulting from exposure to a mitogen, cytokine, chemokine, cellular ligand, or an antigen for which it is specific. GeneOntology

positive regulation of macromolecule biosynthetic process Any process that increases the rate, frequency or extent of the chemical reactions and pathways resulting in the formation of a macromolecule, any molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass. GeneOntology

regulation of gene expression Any process that modulates the frequency, rate or extent of gene expression. Gene expression is the process in which a gene's coding sequence is converted into a mature gene product or products (proteins or RNA). This includes the production of an RNA transcript as well as any processing to produce a mature RNA product or an mRNA (for protein-coding genes) and the translation of that mRNA into protein. Protein maturation is included when required to form an active form of a product from an inactive precursor form. GeneOntology

response to chemical Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a chemical stimulus. GeneOntology

Cellular component:

T cell receptor complex A protein complex that contains a disulfide-linked heterodimer of T cell receptor (TCR) chains, which are members of the immunoglobulin superfamily, and mediates antigen recognition, ultimately resulting in T cell activation. The TCR heterodimer is associated with the CD3 complex, which consists of the nonpolymorphic polypeptides gamma, delta, epsilon, zeta, and, in some cases, eta (an RNA splice variant of zeta) or Fc epsilon chains. GeneOntology

Structure Summary Structural annotations of the participating protein chains.

Entry contents: 2 distinct polypeptide molecules

Chains: B, A

Notes: Chains C, D, E, F, G, H, I, J, K and L were removed as chains A and B represent the biologically relevant interaction.

Chain B

Name: T-cell surface glycoprotein CD3 epsilon chain Disordered Confirmed

Source organism: Homo sapiens

Length: 18 residues

Sequence:Sequence according to PDB SEQRESPDYEPIRKGQRDLYSGLN

The sequence contains the following modified/non-standard residues:

• phosphotyrosine (Y) at position 188 (PDB position: 170)

• phosphotyrosine (Y) at position 199 (PDB position: 181)

UniProtKB AC: P07766 (positions: 186-203) UniProt Coverage: 8.7%

UniRef90 AC: UniRef90_P0776 (positions: 186-203) UniRef90

Chain A

Name: Tyrosine-protein kinase SYK Ordered

Source organism: Homo sapiens

Length: 254 residues

Sequence:Sequence according to PDB SEQRESSANHLPFFFGNITREEAEDYLVQGGMSDGLYLLRQSRNYLGGFALSVAHGRKAHHYTIERELNGTYAIAGGRTHASPADLCHYHSQESDGLVCLLKKPFNRPQGVQPKTGPFEDLKENLIREYVKQTWNLQGQALEQAIISQKPQLEKLIATTAHEKMPWFHGKISREESEQIVLIGSKTNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDKTGKLSIPEGKKFDTLWQLVEHYSYKADGLLRVLTVPCQKI

UniProtKB AC: P43405 (positions: 9-262) UniProt Coverage: 40%

UniRef90 AC: UniRef90_P43405 (positions: 9-262) UniRef90

Evidence Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding.

Chain B: Disordered Confirmed

The 153-207 region described in DisProt entry DP00506 cover 100% of the sequence present in the structure. The protein region involved in the interaction contains a known functional linear motif (ITAM - PF02189).

Chain A: Ordered

The SH2 domain involved in the interaction is known to adopt a stable structure in isolation (see Pfam domain PF00017). A solved monomeric structure of the domain is represented by PDB ID 4fl2.

Related Structure(s) Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap).

No related structure was found in the Protein Data Bank.

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