1csy

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SYK TYROSINE KINASE C-TERMINAL SH2 DOMAIN COMPLEXED WITH A PHOSPHOPEPTIDEFROM THE GAMMA CHAIN OF THE HIGH AFFINITY IMMUNOGLOBIN G RECEPTOR, NMR

Overview

BACKGROUND: Recruitment of the intracellular tyrosine kinase Syk to, activated immune-response receptors is a critical early step in, intracellular signaling. In mast cells, Syk specifically associates with, doubly phosphorylated immunoreceptor tyrosine-based activation motifs, (ITAMs) that are found within the IgE receptor. The mechanism by which Syk, recognizes these motifs is not fully understood. Both Syk SH2 (Src, homology 2) domains are required for high-affinity binding to these, motifs, but the C-terminal SH2 domain (Syk-C) can function independently, and can bind, in isolation, to the tyrosine-phosphorylated IgE receptor in, vitro. In order to improve understanding of the cellular function of Syk, we have determined the solution structure of Syk-C complexed with a, phosphotyrosine peptide derived from the gamma subunit of the IgE, receptor. RESULTS: The Syk-C:peptide structure is compared with liganded, structures of both the SH2 domain of Src and the C-terminal SH2 domain of, ZAP-70 (the 70 kDa zeta-associated protein). The topologies of these, domains are similar, although significant differences occur in the loop, regions. In the Syk-C structure, the phosphotyrosine and leucine residues, of the peptide ligand interact with pockets on the protein, and the, intervening residues are extended. CONCLUSIONS: Syk-C resembles other SH2, domains in its peptide-binding interactions and overall topology, a result, that is consistent with its ability to function as an independent SH2, domain in vitro. This result suggests that Syk-C plays a unique role in, the intact Syk protein. The determinants of the binding affinity and, selectivity of Syk-C may reside in the least-conserved structural elements, that comprise the phosphotyrosine- and leucine-binding sites. These, structural features can be exploited for the design of Syk-selective SH2, antagonists for the treatment of allergic disorders and asthma.

About this Structure

1CSY is a Single protein structure of sequence from Homo sapiens with ACE and NH2 as ligands. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

Reference

Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide., Narula SS, Yuan RW, Adams SE, Green OM, Green J, Philips TB, Zydowsky LD, Botfield MC, Hatada M, Laird ER, et al., Structure. 1995 Oct 15;3(10):1061-73. PMID:8590001

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