Architecture of Eph receptor clusters.
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.
Himanen
Juha P
JP
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Yermekbayeva
Laila
L
Janes
Peter W
PW
Walker
John R
JR
Xu
Kai
K
Atapattu
Lakmali
L
Rajashankar
Kanagalaghatta R
KR
Mensinga
Anneloes
A
Lackmann
Martin
M
Nikolov
Dimitar B
DB
Dhe-Paganon
Sirano
S
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D036382:Ephrin-A1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D036386:Ephrin-A5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D036082:Receptor, EphA1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D036382:Ephrin-A1; D036386:Ephrin-A5; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D036082:Receptor, EphA1; D036104:Receptor, EphA2