Structural Basis for Autoinhibition of the EphB2 Receptor Tyrosine Kinase by the Unphosphorylated Juxtamembrane Region

作者: Leanne E. Wybenga-Groot , Berivan Baskin , Siew Hwa Ong , Jiefei Tong , Tony Pawson

DOI: 10.1016/S0092-8674(01)00496-2

关键词:

摘要: The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and activation segment. We have solved X-ray crystal structure to 1.9 A resolution of an autoinhibited, unphosphorylated form EphB2 comprised domain. structure, supported mutagenesis data, reveals that segment adopts a helical conformation distorts small lobe domain, blocks from attaining activated conformation. Phosphorylation conserved tyrosines would relieve this autoinhibition disturbing association with while liberating phosphotyrosine sites for binding SH2 domains target proteins. propose autoinhibitory mechanism employed more general device through which kinases are controlled.

参考文章(55)
Zbyszek Otwinowski, Wladek Minor, Processing of X-ray diffraction data collected in oscillation mode Methods in Enzymology. ,vol. 276, pp. 307- 326 ,(1997) , 10.1016/S0076-6879(97)76066-X
H Kitayama, Y Kanakura, T Furitsu, T Tsujimura, K Oritani, H Ikeda, H Sugahara, H Mitsui, Y Kanayama, Y Kitamura, Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. Blood. ,vol. 85, pp. 790- 798 ,(1995) , 10.1182/BLOOD.V85.3.790.BLOODJOURNAL853790
S Misawa, S Horiike, K Kashima, H Kaneko, T Iwai, M Nakao, S Yokota, T Fujimoto, Y Sonoda, Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. ,vol. 10, pp. 1911- 1918 ,(1996)
Georg Mellitzer, Qiling Xu, David G. Wilkinson, Eph receptors and ephrins restrict cell intermingling and communication Nature. ,vol. 400, pp. 77- 81 ,(1999) , 10.1038/21907
Frank Sicheri, David Stapleton, Inga Balan, Tony Pawson, The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nature Structural & Molecular Biology. ,vol. 6, pp. 44- 49 ,(1999) , 10.1038/4917
G M Myles, C S Brandt, K Carlberg, L R Rohrschneider, Tyrosine 569 in the c-Fms juxtamembrane domain is essential for kinase activity and macrophage colony-stimulating factor-dependent internalization. Molecular and Cellular Biology. ,vol. 14, pp. 4843- 4854 ,(1994) , 10.1128/MCB.14.7.4843
Fumihiko Hayakawa, Masayuki Towatari, Hitoshi Kiyoi, Mitsune Tanimoto, Toshio Kitamura, Hidehiko Saito, Tomoki Naoe, Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines Oncogene. ,vol. 19, pp. 624- 631 ,(2000) , 10.1038/SJ.ONC.1203354
Tony Pawson, John D Scott, Signaling Through Scaffold, Anchoring, and Adaptor Proteins Science. ,vol. 278, pp. 2075- 2080 ,(1997) , 10.1126/SCIENCE.278.5346.2075