Himanen J P, Henkemeyer M, Nikolov D B
Cellular Biochemistry and Biophysics Program, Memorial-Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nature. 1998 Dec 3;396(6710):486-91. doi: 10.1038/24904.
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.
Eph受体可结合一类称为ephrin的细胞膜锚定配体，是受体酪氨酸激酶（RTK）中最大的亚家族。它们主要在发育中的和成年神经系统中表达，在接触介导的轴突导向、轴突成束和细胞迁移中起重要作用。Eph受体在其他RTK中是独特的，因为它们分为具有不同配体特异性的两个亚类，并且它们自身可以作为配体来激活双向细胞间信号传导。我们在此报告了EphB2受体（也称为Nuk）氨基末端配体结合结构域分辨率为2.9埃的晶体结构。该结构域折叠成由11条反平行β链组成的紧密果冻卷β三明治结构。利用基于结构的诱变，我们鉴定出一个对配体结合和类别特异性很重要的延伸环。这个环在Eph RTK亚类内部保守，但在不同亚类之间不保守，它靠在错义突变导致信号缺陷的位置附近的β三明治凹面表面上，将配体结合区域定位在受体表面。
