1B47

STRUCTURE OF THE N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE IN ZAP-70

Summary for 1B47

• Entry DOI: 10.2210/pdb1b47/pdb
• Descriptor: CBL, CALCIUM ION (3 entities in total)
• Functional Keywords: cbl, signal transduction, sh2, proto-oncogene
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P22681
• Total number of polymer chains: 3
• Total formula weight: 106238.96

Authors

Meng, W.,Sawasdikosol, S.,Burakoff, S.J.,Eck, M.J. (deposition date: 1999-01-06, release date: 1999-04-27, Last modification date: 2024-02-07)

Primary citation

Meng, W.,Sawasdikosol, S.,Burakoff, S.J.,Eck, M.J.
Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase.
Nature, 398:84-90, 1999

PubMed Abstract: 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.

PubMed: 10078535
DOI: 10.1038/18050

Experimental method

X-RAY DIFFRACTION (2.2 Å)