Architecture of Eph receptor clusters.

Publication Type:

Journal Article

Authors:

Himanen, Juha P; Yermekbayeva, Laila; Janes, Peter W; Walker, John R; Xu, Kai; Atapattu, Lakmali; Rajashankar, Kanagalaghatta R; Mensinga, Anneloes; Lackmann, Martin; Nikolov, Dimitar B; Dhe-Paganon, Sirano

Source:

Proc Natl Acad Sci U S A, Volume 107, Issue 24, p.10860-5 (2010)

Keywords:

Amino Acid Sequence, Binding Sites, Cell Line, Crystallography, X-Ray, Ephrin-A1, Ephrin-A5, Humans, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Protein Structure, Secondary, Protein Structure, Tertiary, Receptor, EphA1, Receptor, EphA2, Recombinant Proteins, Signal Transduction

Abstract:

<p>Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development. Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells. However, the structural and mechanistic details of this assembly remained undefined. Here we present high-resolution structures of the complete EphA2 ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster. The structures reveal an elongated architecture with novel Eph/Eph interactions, both within and outside of the Eph ligand-binding domain, that suggest the molecular mechanism underlying Eph/ephrin clustering. Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering.</p>