title: Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.
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.
authors.affiliation: Department of Molecular and Cell Biology, Department of Chemistry, and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Deindl
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kadlecek
authors.forename: Tomas
authors.initials: T
authors.lastname: Brdicka
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Cao
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000502:physiology; D004794:Enzyme Repression / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000201:enzymology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry* / Q000378:metabolism*; D018909:src Homology Domains / Q000502:physiology
chemical_list: D051746:ZAP-70 Protein-Tyrosine Kinase