Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.
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Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J
Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.
Cell. 2007 May 18;129(4):735-46.
- PubMed ID
- 17512407 [ View in PubMed]
- Abstract
ZAP-70, a cytoplasmic tyrosine kinase required for T cell antigen receptor signaling, is controlled by a regulatory segment that includes a tandem SH2 unit responsible for binding to immunoreceptor tyrosine-based activation motifs (ITAMs). The crystal structure of autoinhibited ZAP-70 reveals that the inactive kinase domain adopts a conformation similar to that of cyclin-dependent kinases and Src kinases. The autoinhibitory mechanism of ZAP-70 is, however, distinct and involves interactions between the regulatory segment and the hinge region of the kinase domain that reduce its flexibility. Two tyrosine residues in the SH2-kinase linker that activate ZAP-70 when phosphorylated are involved in aromatic-aromatic interactions that connect the linker to the kinase domain. These interactions are inconsistent with ITAM binding, suggesting that destabilization of this autoinhibited ZAP-70 conformation is the first step in kinase activation.