Structural Basis for Autoinhibition of the EphB2 Receptor Tyrosine Kinase by the Unphosphorylated Juxtamembrane Region
| Autor: | Berivan Baskin, Frank Sicheri, Leanne E. Wybenga-Groot, Tony Pawson, Jiefei Tong, Siew Hwa Ong |
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| Rok vydání: | 2001 |
| Předmět: |
Models
Molecular Protein Conformation Receptor EphB2 Receptor Protein-Tyrosine Kinases Molecular Sequence Data SH2 domain Crystallography X-Ray General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase Protein Structure Secondary MAP2K7 03 medical and health sciences Mice 0302 clinical medicine Animals Humans Amino Acid Sequence Phosphorylation 030304 developmental biology 0303 health sciences Binding Sites biology Sequence Homology Amino Acid Biochemistry Genetics and Molecular Biology(all) Autophosphorylation Cell Membrane Recombinant Proteins Cell biology Biochemistry Protein kinase domain Amino Acid Substitution 030220 oncology & carcinogenesis biology.protein Mutagenesis Site-Directed Sequence Alignment Platelet-derived growth factor receptor Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Cell. 106(6):745-757 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/s0092-8674(01)00496-2 |
| Popis: | The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. We have solved the X-ray crystal structure to 1.9 Å resolution of an autoinhibited, unphosphorylated form of EphB2 comprised of the juxtamembrane region and the kinase domain. The structure, supported by mutagenesis data, reveals that the juxtamembrane segment adopts a helical conformation that distorts the small lobe of the kinase domain, and blocks the activation segment from attaining an activated conformation. Phosphorylation of conserved juxtamembrane tyrosines would relieve this autoinhibition by disturbing the association of the juxtamembrane segment with the kinase domain, while liberating phosphotyrosine sites for binding SH2 domains of target proteins. We propose that the autoinhibitory mechanism employed by EphB2 is a more general device through which receptor tyrosine kinases are controlled. |
| Databáze: | OpenAIRE |
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