Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex.
Ephrin (Eph) receptor tyrosine kinases fall into two subclasses (A and B) according to preferences for their ephrin ligands. All published structural studies of Eph receptor/ephrin complexes involve B-class receptors. Here, we present the crystal structures of an A-class complex between EphA2 and ephrin-A1 and of unbound EphA2. Although these structures are similar overall to their B-class counterparts, they reveal important differences that define subclass specificity. The structures suggest that the A-class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a 'lock-and-key'-type binding mechanism, in contrast to the 'induced fit' mechanism defining the B-class molecules. This model is supported by structure-based mutagenesis and by differential requirements for ligand oligomerization by the two subclasses in cell-based Eph receptor activation assays. Finally, the structure of the unligated receptor reveals a homodimer assembly that might represent EphA2-specific homotypic cell adhesion interactions.
Himanen
Juha P
JP
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Goldgur
Yehuda
Y
Miao
Hui
H
Myshkin
Eugene
E
Guo
Hong
H
Buck
Matthias
M
Nguyen
My
M
Rajashankar
Kanagalaghatta R
KR
Wang
Bingcheng
B
Nikolov
Dimitar B
DB
D000595:Amino Acid Sequence; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D036382:Ephrin-A1 / Q000737:chemistry*; D036383:Ephrin-A2 / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D036081:Receptors, Eph Family / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D055672:Static Electricity
D036382:Ephrin-A1; D036383:Ephrin-A2; D008024:Ligands; D036081:Receptors, Eph Family