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The C2 Domain of PKCδ Is a Phosphotyrosine Binding Domain

2005; Cell Press; Volume: 121; Issue: 2 Linguagem: Inglês

10.1016/j.cell.2005.02.019

1097-4172

Cyril H. Benes, Ning Wu, Andrew E. H. Elia, Tejal Dharia, Lewis C. Cantley, Stephen P. Soltoff,

PI3K/AKT/mTOR signaling in cancer

In eukaryotic cells, the SH2 and PTB domains mediate protein-protein interactions by recognizing phosphotyrosine residues on target proteins. Here we make the unexpected finding that the C2 domain of PKCδ directly binds to phosphotyrosine peptides in a sequence-specific manner. We provide evidence that this domain mediates PKCδ interaction with a Src binding glycoprotein, CDCP1. The crystal structure of the PKCδ C2 domain in complex with an optimal phosphopeptide reveals a new mode of phosphotyrosine binding in which the phosphotyrosine moiety forms a ring-stacking interaction with a histidine residue of the C2 domain. This is also the first example of a protein Ser/Thr kinase containing a domain that binds phosphotyrosine.