title: Crystal structure of the human ephrin-A5 ectodomain.
abstract: The Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, pathfinding, and mobility in the nervous and cardiovascular systems. Recent structural studies have revealed unique molecular features that explain many of the biochemical and signaling properties of Ephs and ephrins. Nevertheless, open questions remain, including understanding the precise molecular mechanism underlining their binding-partner preferences and subclass specificity. In this study, we have determined and present the crystal structure of the extracellular domain of ephrin-A5-the first structure of an unbound A-class ephrin. The structure, determined at 2.1 A resolution, is a variation of the Greek key beta-barrel folding topology, containing eight beta-strands, and stabilized by two disulphide bonds. Overall, ephrin-A5 is structurally very similar to ephrin-B1 and ephrin-B2 but, unlike ephrin-B2, it does not show dimerization either in solution or in the crystals. Comparing free ephrin-A5 to the previously published structure of EphB2-bound ephrin-A5 reveals that significant conformational changes occur only around the G-H ephrin loop that upon binding bends toward the receptor. Interestingly, the G-H loop undergoes a very similar conformational rearrangement in ephrin-B2 upon receptor binding. The results of this study further emphasize the importance of the G-H loop for receptor recognition and selectivity, and could serve as a starting point for the development of structure-based Eph antagonists.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. nikolovd@mskcc.org
authors.forename: Dimitar
authors.initials: D
authors.lastname: Nikolov
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
authors.forename: Philip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Juha
authors.initials: J
authors.lastname: Himanen
mesh_terms: D003460:Crystallization; D018360:Crystallography, X-Ray; D036386:Ephrin-A5 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: D036386:Ephrin-A5; D020794:Receptor Protein-Tyrosine Kinases