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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 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 ofmore » the G-H loop for receptor recognition and selectivity, and could serve as a starting point for the development of structure-based Eph antagonists.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959963
Report Number(s):
BNL-82949-2009-JA
TRN: US201016%%1107
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Protein Science; Journal Volume: 16
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CARDIOVASCULAR SYSTEM; COMMUNICATIONS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DIMERIZATION; PHOSPHOTRANSFERASES; RESOLUTION; SPECIFICITY; TOPOLOGY; TYROSINE; national synchrotron light source

Citation Formats

Nikolov,D., Li, C., Lackmann, M., Jeffrey, P., and Himanen, J.. Crystal Structure of the Human Ephrin-A5 Ectodomain. United States: N. p., 2007. Web. doi:10.1110/ps.062665807.
Nikolov,D., Li, C., Lackmann, M., Jeffrey, P., & Himanen, J.. Crystal Structure of the Human Ephrin-A5 Ectodomain. United States. doi:10.1110/ps.062665807.
Nikolov,D., Li, C., Lackmann, M., Jeffrey, P., and Himanen, J.. Mon . "Crystal Structure of the Human Ephrin-A5 Ectodomain". United States. doi:10.1110/ps.062665807.
@article{osti_959963,
title = {Crystal Structure of the Human Ephrin-A5 Ectodomain},
author = {Nikolov,D. and Li, C. and Lackmann, M. and Jeffrey, P. and Himanen, J.},
abstractNote = {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.},
doi = {10.1110/ps.062665807},
journal = {Protein Science},
number = ,
volume = 16,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}