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The structure, regulation, and function of ZAP-70 |
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| Authors: | Byron B. Au-Yeung Sebastian Deindl Lih-Yun Hsu Emil H. Palacios Susan E. Levin John Kuriyan Arthur Weiss |
| Affiliation: | Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA.; Departments of Molecular and Cell Biology and Chemistry, Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.; Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biomedical Research, University of California San Francisco, San Francisco CA, USA.; Department of Biology, Williams College, Williamstown, MA, USA.; Physical Biosciences Division, Lawrence Berkeley National Lab., Berkeley, CA, USA. |
| Abstract: | Summary: The tyrosine ZAP-70 (ζ-associated protein of 70 kDa) kinase plays a critical role in activating many downstream signal transduction pathways in T cells following T-cell receptor (TCR) engagement. The importance of ZAP-70 is evidenced by the severe combined immunodeficiency that occurs in ZAP-70-deficient mice and humans. In this review, we describe recent analyses of the ZAP-70 crystal structure, revealing a complex regulatory mechanism of ZAP-70 activity, the differential requirements for ZAP-70 and spleen tyrosine kinase (SyK) in early T-cell development, as well as the role of ZAP-70 in chronic lymphocytic leukemia and autoimmunity. Thus, the critical importance of ZAP-70 in TCR signaling and its predominantly T-cell-restricted expression pattern make ZAP-70 an attractive drug target for the inhibition of pathological T-cell responses in disease. |
| Keywords: | ZAP-70 signal transduction T-cell receptor pre-TCR signals autoinhibition ITAM |