Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase

Wuyi Meng, Sansana Sawasdikosol, Steven J. Burakoff and Michael J. Eck ()
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Wuyi Meng: Departments of Biological Chemistry and Molecular Pharmacology and Cancer Biology
Sansana Sawasdikosol: Harvard Medical School, Dana-Farber Cancer Institute
Steven J. Burakoff: Harvard Medical School, Dana-Farber Cancer Institute
Michael J. Eck: Departments of Biological Chemistry and Molecular Pharmacology and Cancer Biology

Nature, 1999, vol. 398, issue 6722, 84-90

Abstract: Abstract Cbl is an adaptor protein that functions as a negative regulator of many signalling pathways that start from receptors at the cell surface1,2,3,4. 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 potential5. In T cells, Cbl-N binds to the tyrosine-phosphorylated inhibitory site of the protein tyrosine kinase ZAP-706. 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-hand7 calcium-binding domain, and a divergent SH2 domain8 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.

Date: 1999
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DOI: 10.1038/18050

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