Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2.
The Eph receptors, which bind a group of cell-membrane-anchored ligands known as ephrins, represent the largest subfamily of receptor tyrosine kinases (RTKs). They are predominantly expressed in the developing and adult nervous system and are important in contact-mediated axon guidance, axon fasciculation and cell migration. Eph receptors are unique among other RTKs in that they fall into two subclasses with distinct ligand specificities, and in that they can themselves function as ligands to activate bidirectional cell-cell signalling. We report here the crystal structure at 2.9 A resolution of the amino-terminal ligand-binding domain of the EphB2 receptor (also known as Nuk). The domain folds into a compact jellyroll beta-sandwich composed of 11 antiparallel beta-strands. Using structure-based mutagenesis, we have identified an extended loop that is important for ligand binding and class specificity. This loop, which is conserved within but not between Eph RTK subclasses, packs against the concave beta-sandwich surface near positions at which missense mutations cause signalling defects, localizing the ligand-binding region on the surface of the receptor.
Himanen
J P
JP
Cellular Biochemistry and Biophysics Program, Memorial-Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Henkemeyer
M
M
Nikolov
D B
DB
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D036386:Ephrin-A5; D036388:Ephrin-B2; D004926:Escherichia coli; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011487:Protein Conformation; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D036183:Receptor, EphB2
D036386:Ephrin-A5; D036388:Ephrin-B2; D008024:Ligands; D008565:Membrane Proteins; D020794:Receptor Protein-Tyrosine Kinases; D036183:Receptor, EphB2