Structural basis for the inhibition of tyrosine kinase activity of ZAP-70.
Cell
; 129(4): 735-46, 2007 May 18.
Article
em En
| MEDLINE
| ID: mdl-17512407
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.
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Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Apresentação de Antígeno
/
Proteína-Tirosina Quinase ZAP-70
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article