Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family.
The receptor Tyro3 together with Axl and Mer form the Axl/Tyro3 family of receptor tyrosine kinases. Members of this family play essential roles in spermatogenesis, immunoregulation, and phagocytosis. Gas6, the product of growth arrest-specific gene, activates the kinase activity of all three receptors. Here, we report the first biochemical and structural characterization of a member of this family, namely of a fragment spanning the two N-terminal Ig domains of the extracellular part of human Tyro3. Its ligand binding specificity profile is identical to the activation profile of the native receptor. The 1.95-A crystal structure suggests a common ligand-binding site in this receptor family located at the interface of the Ig domains and unusually rich in cis-prolines. Furthermore, both in the crystal and in solution we observed the ligand-independent dimerization of the receptor fragment. This homophilic interaction emphasizes previous functional reports, which hinted that in addition to signal transduction, members of this family of receptors might participate in cell adhesion.
Heiring
Christoph
C
Lehrstuhl für Biotechnik, Institut für Mikrobiologie, Biochemie, und Genetik, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91052 Erlangen, Germany.
Dahlbäck
Björn
B
Muller
Yves A
YA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002448:Cell Adhesion; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D006031:Glycosylation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014461:Ultracentrifugation; D000099255:Growth Arrest-Specific Protein 6
D018076:DNA, Complementary; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011392:Proline; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6; C084944:TYRO3 protein, human