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31  structures 91  species 0  interactions 554  sequences 4  architectures

Family: Ephrin (PF00812)

Summary: Ephrin

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Ephrin Edit Wikipedia article

Ephrin
PDB 2hle EBI.jpg
structural and biophysical characterization of the ephb4-ephrinb2 protein protein interaction and receptor specificity.
Identifiers
Symbol Ephrin
Pfam PF00812
Pfam clan CL0026
InterPro IPR001799
PROSITE PDOC01003
SCOP 1kgy
SUPERFAMILY 1kgy
CDD cd02675

Ephrins also known as ephrin ligands or Eph family receptor interacting proteins are a family of proteins that serve as the ligands of the ephrin receptor. Ephrin receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).

Since ephrin ligands (ephrins) and Eph receptors (Ephs) are both membrane-bound proteins, binding and activation of Eph/epherin intracellular signaling pathways can only occur via direct cell-cell interaction. Eph/epherin signaling regulates a variety of biological processes during embryonic development including the guidance of axon growth cones,[1] formation of tissue boundaries,[2] cell migration, and segmentation.[3] Additionally, Eph/epherin signaling has recently been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation,[4] angiogenesis,[5] and stem cell differentiation.[6]

Contents

[edit] Classification

Ephrin ligands are divided into two subclasses of ephrin-A and ephrin-B based on their structure and linkage to the cell membrane. Ephrin-As are anchored to the membrane by a glycosylphosphatidylinositol (GPI) linkage and lack a cytoplasmic domain while ephrin-Bs are attached to the membrane by a single transmembrane domain that contains a short cytoplasmic PDZ-binding motif. The genes that encode the ephrin-A and ephrin-B proteins are designated as EFNA and EFNB respectively. Eph receptors in turn are classified as either EphAs or EphBs based on their binding affinity for either the ephrin-A or ephrin-B ligands.[7]

Of the eight ephrins that have been identified in humans there are five known ephrin-A ligands (ephrin-A1-5) that interact with nine EphAs (EphA1-8 and EphA10) and three ephrin-B ligands (ephrin-B1-3) that interact with five EphBs (EphB1-4 and EphB6).[4][8] Ephs of a particular subclass demonstrate an ability to bind with high affinity to all ephrins of the corresponding subcass, but in general have little to no cross-binding to ephrins of the opposing subclass.[9] However, there are a few exceptions to this intrasubclass binding specificity as it has recently been shown that ephrin-B3 is able bind to and activate EPH receptor A4 and ephrin-A5 can bind to and activate Eph receptor B2.[10] EphAs/ephrin-As typically bind with high affinity, which can partially be attributed to the fact that ephrinAs interact with EphAs by a "lock-and-key" mechanism that requires little conformational change of the EphAs upon ligand binding. In contrast EphBs typically bind with lower affinity than EphAs/ephring-As since they utilize an "induced fit" mechanism that requires a greater conformational change of EphBs to bind ephrin-Bs.[11]

[edit] Function

[edit] Axon guidance

During the development of the central nervous system Eph/ephrin signaling plays a critical role in the cell-cell mediated migration of several types of neuronal axons to their target destinations. Eph/ephrin signaling controls the guidance of neuronal axons through their ability to inhibit the survival of axonal growth cones, which repels the migrating axon away from the site of Eph/ephrin activation.[12] The growth cones of migrating axons do not simply respond to absolute levels of Ephs or ephrins in cells that they contact, but rather respond to relative levels of Eph and ephrin expression,[13] which allows migrating axons that express either Ephs or ephrins to be directed along gradients of Eph or ephrin expressing cells towards a destination where axonal growth cone survival is no longer completely inhibited.[12]

Although Eph-ephrin activation is usually associated with decreased growth cone survival and the repellence of migrating axons, it has recently been demonstrated that growth cone survival does not depend just on Eph-ephrin activation, but rather on the differential effects of "forward" signaling by the Eph receptor or "reverse" signaling by the ephrin ligand on growth cone survival[12][14](see "Ephrin Reverse Signaling" below).

[edit] Retinotopic mapping

The formation of an organized retinotopic map in the superior colliculus (SC) (referred to as the optic tectum in lower vertebrates) requires the proper migration of the axons of retinal ganglion cells (RGCs) from the retina to specific regions in the SC that is mediated by gradients of Eph and ephrin expression in both the SC and in migrating RGCs leaving the retina.[15] The decreased survival of axonal growth cones discussed above allows for a gradient of high posterior to low anterior ephrin-A ligand expression in the SC to direct migrating RGCs axons from the temporal region of the retina that express a high level of EphA receptors toward targets in the anterior SC and RGCs from the nasal retina that have low EphA expression toward their final destination in the posterior SC.[16][17][18] Similarly, a gradient of ephrin-B1 expression along the medial-ventral axis of the SC directs the migration of dorsal and ventral EphB-expressing RGCs to the lateral and medial SC respectively.[19]

[edit] Reverse signaling

One unique property of the ephrin ligands is that many have the capacity to initiate a "reverse" signal that is separate and distinct from the intracellular signal activated in Eph receptor-expressing cells. Although the mechanisms by which "reverse" signaling occurs are not completely understood, both ephrin-As and ephrin-Bs have been shown to mediate cellular responses that are distinct from those associated with activation of their corresponding receptors. Specifically, ephrin-A5 was shown to stimulate growth cone spreading in spinal motor neurons[12] and ephrin-B1 was shown to promote dendritic spine maturation.[20]

[edit] References

  1. ^ Egea, J.; Klein, R. D. (2007). "Bidirectional Eph–ephrin signaling during axon guidance". Trends in Cell Biology 17 (5): 230–238. doi:10.1016/j.tcb.2007.03.004. PMID 17420126.  edit
  2. ^ Rohani, N.; Canty, L.; Luu, O.; Fagotto, F. O.; Winklbauer, R. (2011). "EphrinB/EphB Signaling Controls Embryonic Germ Layer Separation by Contact-Induced Cell Detachment". In Hamada, Hiroshi. PLoS Biology 9 (3): e1000597. doi:10.1371/journal.pbio.1000597. PMC 3046958. PMID 21390298.  edit
  3. ^ Davy, A.; Soriano, P. (2005). "Ephrin signaling in vivo: Look both ways". Developmental Dynamics 232 (1): 1–10. doi:10.1002/dvdy.20200. PMID 15580616.  edit
  4. ^ a b Kullander, K.; Klein, R. D. (2002). "Mechanisms and functions of eph and ephrin signalling". Nature Reviews Molecular Cell Biology 3 (7): 475–486. doi:10.1038/nrm856. PMID 12094214.  edit
  5. ^ Kuijper, S.; Turner, C. J.; Adams, R. H. (2007). "Regulation of Angiogenesis by Eph–Ephrin Interactions". Trends in Cardiovascular Medicine 17 (5): 145–151. doi:10.1016/j.tcm.2007.03.003. PMID 17574121.  edit
  6. ^ Genander, M.; Frisén, J. (2010). "Ephrins and Eph receptors in stem cells and cancer". Current Opinion in Cell Biology 22 (5): 611–616. doi:10.1016/j.ceb.2010.08.005. PMID 20810264.  edit
  7. ^ Ephnomenclaturecommittee (1997). "Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee". Cell 90 (3): 403–404. doi:10.1016/S0092-8674(00)80500-0. PMID 9267020.  edit
  8. ^ Pitulescu, M. E.; Adams, R. H. (2010). "Eph/ephrin molecules—a hub for signaling and endocytosis". Genes & Development 24 (22): 2480–2492. doi:10.1101/gad.1973910. PMC 2975924. PMID 21078817.  edit
  9. ^ Pasquale, E. B. (1997). "The Eph family of receptors". Current opinion in cell biology 9 (5): 608–615. doi:10.1016/S0955-0674(97)80113-5. PMID 9330863.  edit
  10. ^ Himanen, J. P.; Chumley, M. J.; Lackmann, M.; Li, C.; Barton, W. A.; Jeffrey, P. D.; Vearing, C.; Geleick, D. et al. (2004). "Repelling class discrimination: Ephrin-A5 binds to and activates EphB2 receptor signaling". Nature Neuroscience 7 (5): 501–509. doi:10.1038/nn1237. PMID 15107857.   edit
  11. ^ Himanen, J. P. (2011). "Ectodomain structures of Eph receptors". Seminars in Cell & Developmental Biology 23 (1): 35–42. doi:10.1016/j.semcdb.2011.10.025. PMID 22044883.  edit
  12. ^ a b c d Marquardt, T.; Shirasaki, R.; Ghosh, S.; Andrews, S. E.; Carter, N.; Hunter, T.; Pfaff, S. L. (2005). "Coexpressed EphA Receptors and Ephrin-A Ligands Mediate Opposing Actions on Growth Cone Navigation from Distinct Membrane Domains". Cell 121 (1): 127–139. doi:10.1016/j.cell.2005.01.020. PMID 15820684.  edit
  13. ^ Reber, M. L.; Burrola, P.; Lemke, G. (2004). "A relative signalling model for the formation of a topographic neural map". Nature 431 (7010): 847–853. doi:10.1038/nature02957. PMID 15483613.  edit
  14. ^ Petros, T. J.; Bryson, J. B.; Mason, C. (2010). "Ephrin-B2 elicits differential growth cone collapse and axon retraction in retinal ganglion cells from distinct retinal regions". Developmental Neurobiology 70 (11): 781–794. doi:10.1002/dneu.20821. PMC 2930402. PMID 20629048.  edit
  15. ^ Triplett, J. W.; Feldheim, D. A. (2011). "Eph and ephrin signaling in the formation of topographic maps". Seminars in Cell & Developmental Biology 23 (1): 7–15. doi:10.1016/j.semcdb.2011.10.026. PMID 22044886.  edit
  16. ^ Wilkinson, D. G. (2001). "Multiple roles of EPH receptors and ephrins in neural development". Nature Reviews Neuroscience 2 (3): 155–164. doi:10.1038/35058515. PMID 11256076.  edit
  17. ^ Cheng, H. J.; Nakamoto, M.; Bergemann, A. D.; Flanagan, J. G. (1995). "Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map". Cell 82 (3): 371–381. doi:10.1016/0092-8674(95)90426-3. PMID 7634327.  edit
  18. ^ Drescher, U.; Kremoser, C.; Handwerker, C.; Löschinger, J.; Noda, M.; Bonhoeffer, F. (1995). "In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases". Cell 82 (3): 359–370. doi:10.1016/0092-8674(95)90425-5. PMID 7634326.  edit
  19. ^ Mann, F.; Ray, S.; Harris, W.; Holt, C. (2002). "Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrin-B ligands". Neuron 35 (3): 461–473. doi:10.1016/S0896-6273(02)00786-9. PMID 12165469.  edit
  20. ^ Segura, I.; Essmann, C. L.; Weinges, S.; Acker-Palmer, A. (2007). "Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation". Nature Neuroscience 10 (3): 301–310. doi:10.1038/nn1858. PMID 17310244.  edit

This article incorporates text from the public domain Pfam and InterPro IPR001799

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Ephrin Provide feedback

No Pfam abstract.

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001799

Ephrins are a family of proteins [PUBMED:7838529] that are ligands of class V (EPH-related) receptor protein-tyrosine kinases. These receptors and their ligands have been implicated in regulating neuronal axon guidance and in patterning of the developing nervous system and may also serve a patterning and compartmentalisation role outside of the nervous system as well.

Ephrins are membrane-attached proteins of 205 to 340 residues. Attachment appears to be crucial for their normal function. Type-A ephrins are linked to the membrane via a glycosylphosphatidylinositol (GPI)-linkage, while type-B ephrins are type-I membrane proteins.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan CU_oxidase (CL0026), which has the following description:

Many of the proteins in this family contain multiple similar copies of this plastocyanin-like domain.

The clan contains the following 9 members:

Copper-bind COX2 Cu-oxidase Cu-oxidase_2 Cu-oxidase_3 Cu_bind_like Cupredoxin_1 Ephrin SoxE

Alignments

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  Seed
(14)
Full
(554)
Representative proteomes NCBI
(430)
Meta
(1)
RP15
(47)
RP35
(74)
RP55
(164)
RP75
(288)
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  Seed
(14)
Full
(554)
Representative proteomes NCBI
(430)
Meta
(1)
RP15
(47)
RP35
(74)
RP55
(164)
RP75
(288)
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Curation and family details

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Seed source: Pfam-B_1390 (release 2.1)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 14
Number in full: 554
Average length of the domain: 131.80 aa
Average identity of full alignment: 39 %
Average coverage of the sequence by the domain: 52.16 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.2 25.7
Noise cut-off 24.8 23.8
Model length: 146
Family (HMM) version: 12
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Species distribution

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ephrin domain has been found. There are 31 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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