Crystal Structure of the Human Ephrin-A5 Ectodomain

Journal Article · Mon Jan 01 04:00:00 EST 2007 · Protein Science

DOI:https://doi.org/10.1110/ps.062665807· OSTI ID:959963

Nikolov, D; Li, C; Lackmann, M; Jeffrey, P; Himanen, J

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 Angstroms 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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959963
• Report Number(s): BNL--82949-2009-JA
• Journal Information: Protein Science, Journal Name: Protein Science Vol. 16
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CARDIOVASCULAR SYSTEM
COMMUNICATIONS
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
DIMERIZATION
PHOSPHOTRANSFERASES
RESOLUTION
SPECIFICITY
TOPOLOGY
TYROSINE
national synchrotron light source