Structural Plasticity of Eph Receptor A4 Facilitates Cross-class Ephrin Signaling

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2009 Oct 20

PMID 19836338

Citations 59

Authors

Thomas A Bowden

A Radu Aricescu

Joanne E Nettleship

Christian Siebold

Nahid Rahman-Huq

Raymond J Owens

David I Stuart

E Yvonne Jones

Affiliations

Soon will be listed here.

Abstract

The EphA4 tyrosine kinase cell surface receptor regulates an array of physiological processes and is the only currently known class A Eph receptor that binds both A and B class ephrins with high affinity. We have solved the crystal structure of the EphA4 ligand binding domain alone and in complex with (1) ephrinB2 and (2) ephrinA2. This set of structures shows that EphA4 has significant conformational plasticity in its ligand binding face. In vitro binding data demonstrate that it has a higher affinity for class A than class B ligands. Structural analyses, drawing on previously reported Eph receptor structures, show that EphA4 in isolation and in complex with ephrinA2 resembles other class A Eph receptors but on binding ephrinB2 assumes structural hallmarks of the class B Eph receptors. This interactive plasticity reveals EphA4 as a structural chameleon, able to adopt both A and B class Eph receptor conformations, and thus provides a molecular basis for EphA-type cross-class reactivity.

Citing Articles

Master regulators of neurogenesis: the dynamic roles of Ephrin receptors across diverse cellular niches.

Rasool D, Jahani-Asl A Transl Psychiatry. 2024; 14(1):462.

PMID: 39505843 PMC: 11541728. DOI: 10.1038/s41398-024-03168-4.

Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity.

Zhang S, Zhao J, Sha W, Zhang X, Mai J, Bartlett P J Cereb Blood Flow Metab. 2023; 44(3):419-433.

PMID: 37871622 PMC: 10870966. DOI: 10.1177/0271678X231209607.

Structural insights into EphA4 unconventional activation from prediction of the EphA4 and its complex with ribonuclease 1.

Li Y, Yamaguchi H, Liu Y, Hsu K, Sun T, Sun P Am J Cancer Res. 2022; 12(10):4865-4878.

PMID: 36381327 PMC: 9641407.

EphrinA4 mimetic peptide impairs fear conditioning memory reconsolidation in lateral amygdala.

Mana R, Ilovich O, Dines M, Lamprecht R Sci Rep. 2022; 12(1):17731.

PMID: 36273074 PMC: 9588004. DOI: 10.1038/s41598-022-21519-3.

EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes.

Dennys C, Baggio C, Rodrigo R, Roussel F, Kulinich A, Heintzman S iScience. 2022; 25(9):104877.

PMID: 36034213 PMC: 9404653. DOI: 10.1016/j.isci.2022.104877.

References

Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T . EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci U S A. 1998; 95(22):13248-53. PMC: 23772. DOI: 10.1073/pnas.95.22.13248. View

Chrencik J, Brooun A, Recht M, Kraus M, Koolpe M, Kolatkar A . Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity. Structure. 2006; 14(2):321-30. DOI: 10.1016/j.str.2005.11.011. View

Graham S, Bahar M, Cooray S, Chen R, Whalen D, Abrescia N . Vaccinia virus proteins A52 and B14 Share a Bcl-2-like fold but have evolved to inhibit NF-kappaB rather than apoptosis. PLoS Pathog. 2008; 4(8):e1000128. PMC: 2494871. DOI: 10.1371/journal.ppat.1000128. View

Coulthard M, Duffy S, Down M, Evans B, Power M, Smith F . The role of the Eph-ephrin signalling system in the regulation of developmental patterning. Int J Dev Biol. 2002; 46(4):375-84. View

Gouet P, Courcelle E, Stuart D, Metoz F . ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics. 1999; 15(4):305-8. DOI: 10.1093/bioinformatics/15.4.305. View

Lu Q, Sun E, Klein R, Flanagan J . Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell. 2001; 105(1):69-79. DOI: 10.1016/s0092-8674(01)00297-5. View

Himanen J, Chumley M, Lackmann M, Li C, Barton W, Jeffrey P . Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci. 2004; 7(5):501-9. DOI: 10.1038/nn1237. View

Himanen J, Rajashankar K, Lackmann M, Cowan C, Henkemeyer M, Nikolov D . Crystal structure of an Eph receptor-ephrin complex. Nature. 2002; 414(6866):933-8. DOI: 10.1038/414933a. View

Stuart D, Levine M, MUIRHEAD H, Stammers D . Crystal structure of cat muscle pyruvate kinase at a resolution of 2.6 A. J Mol Biol. 1979; 134(1):109-42. DOI: 10.1016/0022-2836(79)90416-9. View

10.

Berrow N, Alderton D, Sainsbury S, Nettleship J, Assenberg R, Rahman N . A versatile ligation-independent cloning method suitable for high-throughput expression screening applications. Nucleic Acids Res. 2007; 35(6):e45. PMC: 1874605. DOI: 10.1093/nar/gkm047. View

11.

Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F . A novel putative tyrosine kinase receptor encoded by the eph gene. Science. 1987; 238(4834):1717-20. DOI: 10.1126/science.2825356. View

12.

Lim Y, McLaughlin T, Sung T, Santiago A, Lee K, OLeary D . p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron. 2008; 59(5):746-58. PMC: 2677386. DOI: 10.1016/j.neuron.2008.07.032. View

13.

Day B, To C, Himanen J, Smith F, Nikolov D, Boyd A . Three distinct molecular surfaces in ephrin-A5 are essential for a functional interaction with EphA3. J Biol Chem. 2005; 280(28):26526-32. DOI: 10.1074/jbc.M504972200. View

14.

Himanen J, Goldgur Y, Miao H, Myshkin E, Guo H, Buck M . Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex. EMBO Rep. 2009; 10(7):722-8. PMC: 2727437. DOI: 10.1038/embor.2009.91. View

15.

Qin H, Shi J, Noberini R, Pasquale E, Song J . Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor. J Biol Chem. 2008; 283(43):29473-84. PMC: 2662028. DOI: 10.1074/jbc.M804114200. View

16.

Corpet F . Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 1988; 16(22):10881-90. PMC: 338945. DOI: 10.1093/nar/16.22.10881. View

17.

Gale N, Holland S, Valenzuela D, Flenniken A, Pan L, Ryan T . Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron. 1996; 17(1):9-19. DOI: 10.1016/s0896-6273(00)80276-7. View

18.

Cowan C, Henkemeyer M . Ephrins in reverse, park and drive. Trends Cell Biol. 2002; 12(7):339-46. DOI: 10.1016/s0962-8924(02)02317-6. View

19.

Aricescu A, Lu W, Jones E . A time- and cost-efficient system for high-level protein production in mammalian cells. Acta Crystallogr D Biol Crystallogr. 2006; 62(Pt 10):1243-50. DOI: 10.1107/S0907444906029799. View

20.

Noberini R, Koolpe M, Peddibhotla S, Dahl R, Su Y, Cosford N . Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J Biol Chem. 2008; 283(43):29461-72. PMC: 2570887. DOI: 10.1074/jbc.M804103200. View