2k1l
NMR structures of dimeric transmembrane domain of the receptor tyrosine kinase EphA1 in lipid bicelles at pH 6.3
Structural highlights
FunctionEPHA1_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. Binds with a low affinity EFNA3 and EFNA4 and with a high affinity to EFNA1 which most probably constitutes its cognate/functional ligand. Upon activation by EFNA1 induces cell attachment to the extracellular matrix inhibiting cell spreading and motility through regulation of ILK and downstream RHOA and RAC. Plays also a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis.[1] [2] [3] Publication Abstract from PubMedEph receptors are found in a wide variety of cells in developing and mature tissues and represent the largest family of receptor tyrosine kinases, regulating cell shape, movements, and attachment. The receptor tyrosine kinases conduct biochemical signals across plasma membrane via lateral dimerization, in which their transmembrane domains play an important role. Structural-dynamic properties of the homodimeric transmembrane domain of the EphA1 receptor were investigated with the aid of solution NMR in lipid bicelles and molecular dynamics in explicit lipid bilayer. EphA1 transmembrane segments associate in a right-handed parallel a-helical bundle (544-569)(2) through the N-terminal glycine zipper motif A(550)X(sub3}G(554)X(sub3}G(super558}. Under acidic conditions, the N-terminus of the transmembrane helix is stabilized by an N-capping box formed by uncharged carboxyl group of Glu(547), while its deprotonation results in a rearrangement of hydrogen bonds, fractional unfolding of the helix, and a realignment of the helix-helix packing with appearance of additional minor dimer conformation employing seemingly the C-terminal GG4-like dimerization motif A(560)X(sub3}G(super564}. This can be interpreted as ability of the EphA1 receptor to adjust its response to ligand binding according to extracellular pH. The dependence of the pKa value of Glu(super547} and the dimer conformational equilibrium on the lipid head charge suggests that both local environment and membrane surface potential can modulate dimerization and activation of the receptor. This makes the EphA1 receptor unique among Eph family, implying its possible physiological role as an "extracellular pH sensor", and can have relevant physiological implications. Spatial structure and pH-dependent conformational diversity of dimeric transmembrane domain of the receptor tyrosine kinase EphA1.,Bocharov EV, Mayzel ML, Volynsky PE, Goncharuk MV, Ermolyuk YS, Schulga AA, Artemenko EO, Efremov RG, Arseniev AS J Biol Chem. 2008 Aug 26. PMID:18728013[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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