Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.

Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J

Cell 129 (4) 735-746 [2007-05-18; online 2007-05-22]

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.

SciLifeLab Fellow

Sebastian Deindl

PubMed 17512407

DOI 10.1016/j.cell.2007.03.039

Crossref 10.1016/j.cell.2007.03.039

pii: S0092-8674(07)00455-2

Publications 7.2.9