1b47
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STRUCTURE OF THE N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE IN ZAP-70
OverviewOverview
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.
About this StructureAbout this Structure
1B47 is a Single protein structure of sequence from Homo sapiens with CA as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase., Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ, Nature. 1999 Mar 4;398(6722):84-90. PMID:10078535
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