PDBsum entry 1shx

Hormone/growth factor

PDB id: 1shx

Contents

Protein chains

138 a.a.

Ligands

NAG-NAG-NAG

NAG-NAG

Waters ×105

References listed in PDB file

Key reference

• Title: Three distinct molecular surfaces in ephrin-A5 are essential for a functional interaction with epha3.
• Authors: B.Day, C.To, J.P.Himanen, F.M.Smith, D.B.Nikolov, A.W.Boyd, M.Lackmann.
• Ref.: J Biol Chem, 2005, 280, 26526-26532.
• PubMed id: 15901737

Abstract

Eph receptor tyrosine kinases (Ephs) function as molecular relays that interact with cell surface-bound ephrin ligands to direct the position of migrating cells. Structural studies revealed that, through two distinct contact surfaces on opposite sites of each protein, Eph and ephrin binding domains assemble into symmetric, circular heterotetramers. However, Eph signal initiation requires the assembly of higher order oligomers, suggesting additional points of contact. By screening a random library of EphA3 binding-compromised ephrin-A5 mutants, we have now determined ephrin-A5 residues that are essential for the assembly of high affinity EphA3 signaling complexes. In addition to the two interfaces predicted from the crystal structure of the homologous EphB2.ephrin-B2 complex, we identified a cluster of 10 residues on the ephrin-A5 E alpha-helix, the E-F loop, the underlying H beta-strand, as well as the nearby B-C loop, which define a distinct third surface required for oligomerization and activation of EphA3 signaling. Together with a corresponding third surface region identified recently outside of the minimal ephrin binding domain of EphA3, our findings provide experimental evidence for the essential contribution of three distinct protein-interaction interfaces to assemble functional EphA3 signaling complexes.

Secondary reference #1

• Title: Eph-Ephrin promiscuity is now crystal clear.
• Author: E.B.Pasquale.
• Ref.: Nat Neurosci, 2004, 7, 417-418. [DOI no: 10.1038/nn0504-417]
• PubMed id: 15114347

Figure 1.
Figure 1. Binding interactions and sequence relationships of Eph receptors and ephrins. Yellow and purple indicate high binding affinity to partners of the A or B subclass, respectively; yellow with a purple center indicates high binding affinity to partners of the A subclass and lower binding affinity to partners of the B subclass; and purple with a yellow center indicates high binding affinity to partners of the B subclass and lower binding affinity to partners of the A subclass. The question mark indicates that the binding preference of the EphA10 receptor^15 has not yet been determined. Eph receptors and ephrins are arranged according to the phylogenetic trees determined using the Clustal program. The dendrogram for the Eph receptors was constructed using the sequences of the ephrin-binding domains^5 of the human Eph receptors, and the dendrogram for the ephrins was constructed using the sequences of the Eph receptor-binding domains^5 of the human ephrins. The lengths of the horizontal branches are proportional to sequence divergence between proteins and the arrangement of the branches indicates putative phylogenetic relationships. EphA9, EphB5 and ephrin-A6 are not shown because these proteins were identified in chicken and do not appear to be present in the human and mouse genomes.

The above figure is reproduced from the cited reference with permission from Macmillan Publishers Ltd