EPHA4_HUMAN » Ephrin type-A receptor 4

EPHA4_HUMAN » Ephrin type-A receptor 4
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
EPHA4_HUMAN » Ephrin type-A receptor 4 » Tyrosine-protein kinase receptor SEK;Receptor protein-tyrosine kinase HEK8;Tyrosine-protein kinase TYRO1;
Hydrophobic Thickness 30.4 ± 2.0 Å
Tilt Angle 1 ± 0°
ΔGtransfer -49.4 kcal/mol
ΔGfold -19.6 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 549-572 (542-579)
Pathways

Axon guidance (KEGG)

PDB 4bk4 (20-547), 4m4p (27-543), 2lw8 (29-209), 2wo1 (30-202), 4w4z (A/B/C/D=29-204), 4w50 (A/B/C/D=29-204), 4bkf (A/B=20-547), 3ckh (A/B=29-209), 4m4r (A/C/E/G=27-543), 4bka (A=20-547), 4bk5 (A=20-547), 3gxu (A=29-203), 2wo3 (A=30-202), 2wo2 (A=30-202)
OPM none
Complexes

EFNB2:EPHA4_HUMAN

EFNB3:EPHA4_HUMAN

Interactions

EFNB2, Complex: EFNB2:EPHA4, PDBID: 2wo2

EFNB3, Complex: EFNB3:EPHA4, PDBID: 4bkf, PubMed

FGFR1, Complex: FGFR1:EPHA4, PubMed

FGFR2, Complex: EPHA4:FGFR2, PubMed

FGFR3, Complex: EPHA4:FGFR3, PubMed

FGFR4, Complex: EPHA4:FGFR4, PubMed

RYK, Complex: RYK:EPHA4, PubMed

Domains

AA: 31-204, PDBID: 2LW8, Subunit A, Seq Identity:100%, Ephrin receptor ligand binding domain

AA: 330-424, PDBID: 4BK4, Subunit A, Seq Identity:100%, Fibronectin type III domain

AA: 442-525, PDBID: 4BK4, Subunit A, Seq Identity:100%, Fibronectin type III domain

AA: 548-618, PDBID: 2HEL, Subunit A, Seq Identity:100%, Ephrin type-A receptor 2 transmembrane domain

AA: 621-878, PDBID: 2HEL, Subunit A, Seq Identity:100%, Protein tyrosine kinase

AA: 908-973, PDBID: 1B0X, Subunit A, Seq Identity:95%, SAM domain (Sterile alpha motif)

UniProt annotation for EPHA4_HUMAN » Ephrin type-A receptor 4
FUNCTION: Receptor tyrosine kinase which binds membrane-bound ephrin 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. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at "Tyr-15" which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

SUBUNIT: Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts (phosphorylated at position Tyr-602) with FYN. Interacts with CDK5, CDK5R1 and NGEF; upon activation by EFNA1 induces NGEF phosphorylation by the kinase CDK5. Interacts with CHN1; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation (By similarity). Interacts (via PDZ motif) with SIPA1L1 (via PDZ domain); controls neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B or RAP2C) GTPases.

TISSUE SPECIFICITY: Ubiquitous.

DOMAIN: The protein kinase domain mediates interaction with NGEF.

UniProt features for EPHA4_HUMAN » Ephrin type-A receptor 4
SIGNAL 1 19 Potential.
CHAIN 20 986 Ephrin type-A receptor 4.
DOMAIN 30 209 Eph LBD.
DOMAIN 328 433 Fibronectin type-III 1.
DOMAIN 441 532 Fibronectin type-III 2.
DOMAIN 621 882 Protein kinase.
DOMAIN 911 975 SAM.
MOTIF 984 986 PDZ-binding (Potential).
ACT_SITE 746 746 Proton acceptor (By similarity).
Amino Acid Sequence for EPHA4_HUMAN » Ephrin type-A receptor 4
MAGIFYFALF SCLFGICDAV TGSRVYPANE VTLLDSRSVQ GELGWIASPL EGGWEEVSIM DEKNTPIRTY QVCNVMEPSQ NNWLRTDWIT REGAQRVYIE IKFTLRDCNS LPGVMGTCKE TFNLYYYESD NDKERFIREN QFVKIDTIAA DESFTQVDIG DRIMKLNTEI RDVGPLSKKG FYLAFQDVGA CIALVSVRVF YKKCPLTVRN LAQFPDTITG ADTSSLVEVR GSCVNNSEEK DVPKMYCGAD GEWLVPIGNC LCNAGHEERS GECQACKIGY YKALSTDATC AKCPPHSYSV WEGATSCTCD RGFFRADNDA ASMPCTRPPS APLNLISNVN ETSVNLEWSS PQNTGGRQDI SYNVVCKKCG AGDPSKCRPC GSGVHYTPQQ NGLKTTKVSI TDLLAHTNYT FEIWAVNGVS KYNPNPDQSV SVTVTTNQAA PSSIALVQAK EVTRYSVALA WLEPDRPNGV ILEYEVKYYE KDQNERSYRI VRTAARNTDI KGLNPLTSYV FHVRARTAAG YGDFSEPLEV TTNTVPSRII GDGANSTVLL VSVSGSVVLV VILIAAFVIS RRRSKYSKAK QEADEEKHLN QGVRTYVDPF TYEDPNQAVR EFAKEIDASC IKIEKVIGVG EFGEVCSGRL KVPGKREICV AIKTLKAGYT DKQRRDFLSE ASIMGQFDHP NIIHLEGVVT KCKPVMIITE YMENGSLDAF LRKNDGRFTV IQLVGMLRGI GSGMKYLSDM SYVHRDLAAR NILVNSNLVC KVSDFGMSRV LEDDPEAAYT TRGGKIPIRW TAPEAIAYRK FTSASDVWSY GIVMWEVMSY GERPYWDMSN QDVIKAIEEG YRLPPPMDCP IALHQLMLDC WQKERSDRPK FGQIVNMLDK LIRNPNSLKR TGTESSRPNT ALLDPSSPEF SAVVSVGDWL QAIKMDRYKD NFTAAGYTTL EAVVHVNQED LARIGITAIT HQNKILSSVQ AMRTQMQQMH GRMVPV