3hpn
From Proteopedia
Ligand recognition by A-class EPH receptors: crystal structures of the EPHA2 ligand-binding domain and the EPHA2/EPHRIN-A1 complex
Structural highlights
Disease[EPHA2_HUMAN] Genetic variations in EPHA2 are the cause of susceptibility to cataract cortical age-related type 2 (ARCC2) [MIM:613020]. A developmental punctate opacity common in the cortex and present in most lenses. The cataract is white or cerulean, increases in number with age, but rarely affects vision.[1] [2] Defects in EPHA2 are the cause of cataract posterior polar type 1 (CTPP1) [MIM:116600]. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.[3] [4] [5] [6] Note=Overexpressed in several cancer types and promotes malignancy.[7] Function[EPHA2_HUMAN] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.[8] [9] [10] [11] [12] [13] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedEphrin (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. Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex.,Himanen JP, Goldgur Y, Miao H, Myshkin E, Guo H, Buck M, Nguyen M, Rajashankar KR, Wang B, Nikolov DB EMBO Rep. 2009 Jul;10(7):722-8. Epub 2009 Jun 12. PMID:19525919[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Receptor protein-tyrosine kinase | Buck, M | Goldgur, Y | Guo, H | Himanen, J P | Miao, H | Myshkin, E | Nguyen, M | Nikolov, D B | Rajashankar, K R | Wang, B | Atp-binding | Eph receptor tyrosine kinase | Ephrin | Glycoprotein | Kinase | Membrane | Nucleotide-binding | Phosphoprotein | Receptor | Transferase | Transmembrane | Tyrosine-protein kinase
