| Structural highlights
6nk0 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.53Å |
| Ligands: | ACA, BAL, EDO, GOL, NH2, PEG |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
The EPH receptor A2 (EphA2) receptor tyrosine kinase plays an important role in a plethora of biological and disease processes, ranging from angiogenesis and cancer to inflammation and parasitic infections. EphA2 is therefore considered an important drug target. Two short peptides previously identified by phage display, named YSA and SWL, are widely used as EphA2-targeting agents owing to their high specificity for this receptor. However, these peptides have only modest (micromolar) potency. Lack of structural information on the binding interactions of YSA and SWL with the extracellular EphA2 ligand-binding domain (LBD) has for many years precluded structure-guided improvements. We now report the high-resolution (1.53-2.20 A) crystal structures of the YSA peptide and several of its improved derivatives in complex with the EphA2 LBD, disclosing that YSA targets the ephrin-binding pocket of EphA2 and mimics binding features of the ephrin-A ligands. The structural information obtained enabled iterative peptide modifications conferring low nanomolar potency. Furthermore, contacts observed in the crystal structures shed light on how C-terminal features can convert YSA derivatives from antagonists to agonists that likely bivalently interact with two EphA2 molecules to promote receptor oligomerization, autophosphorylation, and downstream signaling. Consistent with this model, quantitative FRET measurements in live cells revealed that the peptide agonists promote the formation of EphA2 oligomeric assemblies. Our findings now enable rational strategies to differentially modify EphA2 signaling toward desired outcomes by using appropriately engineered peptides. Such peptides could be used as research tools to interrogate EphA2 function and develop pharmacological leads.
Engineering Nanomolar Peptide LigandsThat Differentially Modulate EphA2 Receptor Signaling.,Gomez-Soler M, Petersen Gehring M, Lechtenberg BC, Zapata-Mercado E, Hristova K, Pasquale EB J Biol Chem. 2019 Apr 23. pii: RA119.008213. doi: 10.1074/jbc.RA119.008213. PMID:31015204[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
- ↑ Jun G, Guo H, Klein BE, Klein R, Wang JJ, Mitchell P, Miao H, Lee KE, Joshi T, Buck M, Chugha P, Bardenstein D, Klein AP, Bailey-Wilson JE, Gong X, Spector TD, Andrew T, Hammond CJ, Elston RC, Iyengar SK, Wang B. EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS Genet. 2009 Jul;5(7):e1000584. doi: 10.1371/journal.pgen.1000584. Epub 2009 , Jul 31. PMID:19649315 doi:10.1371/journal.pgen.1000584
- ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
- ↑ Shiels A, Bennett TM, Knopf HL, Maraini G, Li A, Jiao X, Hejtmancik JF. The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis. 2008;14:2042-55. Epub 2008 Nov 12. PMID:19005574
- ↑ Zhang T, Hua R, Xiao W, Burdon KP, Bhattacharya SS, Craig JE, Shang D, Zhao X, Mackey DA, Moore AT, Luo Y, Zhang J, Zhang X. Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract. Hum Mutat. 2009 May;30(5):E603-11. doi: 10.1002/humu.20995. PMID:19306328 doi:10.1002/humu.20995
- ↑ Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R. Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS One. 2012;7(5):e36564. doi: 10.1371/journal.pone.0036564. Epub 2012 May 3. PMID:22570727 doi:10.1371/journal.pone.0036564
- ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
- ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
- ↑ Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005 Dec 23;280(51):42375-82. Epub 2005 Oct 18. PMID:16236711 doi:10.1074/jbc.M503786200
- ↑ Zhang G, Njauw CN, Park JM, Naruse C, Asano M, Tsao H. EphA2 is an essential mediator of UV radiation-induced apoptosis. Cancer Res. 2008 Mar 15;68(6):1691-6. doi: 10.1158/0008-5472.CAN-07-2372. PMID:18339848 doi:10.1158/0008-5472.CAN-07-2372
- ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
- ↑ Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol. 2010 Aug 9;190(3):461-77. doi: 10.1083/jcb.201005141. Epub 2010 Aug , 2. PMID:20679435 doi:10.1083/jcb.201005141
- ↑ Lin S, Gordon K, Kaplan N, Getsios S. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1. Mol Biol Cell. 2010 Nov 15;21(22):3902-14. doi: 10.1091/mbc.E10-03-0242. Epub, 2010 Sep 22. PMID:20861311 doi:10.1091/mbc.E10-03-0242
- ↑ Gomez-Soler M, Petersen Gehring M, Lechtenberg BC, Zapata-Mercado E, Hristova K, Pasquale EB. Engineering Nanomolar Peptide LigandsThat Differentially Modulate EphA2 Receptor Signaling. J Biol Chem. 2019 Apr 23. pii: RA119.008213. doi: 10.1074/jbc.RA119.008213. PMID:31015204 doi:https://dx.doi.org/10.1074/jbc.RA119.008213
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