2CBL

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

Summary for 2CBL

• Entry DOI: 10.2210/pdb2cbl/pdb
• Descriptor: PROTO-ONCOGENE CBL, ZAP-70, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: proto-oncogene, signal transduction, phosphotyrosine binding, sh2, complex (proto-oncogene-peptide), complex (proto-oncogene-peptide) complex, complex (proto-oncogene/peptide)
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P22681
• Total number of polymer chains: 2
• Total formula weight: 36814.31

Authors

Meng, W.,Sawasdikosol, S.,Burakoff, S.J.,Eck, M.J. (deposition date: 1998-08-28, release date: 1999-05-18, Last modification date: 2024-10-30)

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 (2.1 Å)