PDBsum entry 2k1k

Signaling protein

PDB id: 2k1k

Contents

Protein chain

38 a.a.

PDB id:

2k1k

Name:

Signaling protein

Title:

Nmr structures of dimeric transmembrane domain of the receptor tyrosine kinase epha1 in lipid bicelles at ph 4.3

Structure:

Ephrin type-a receptor 1. Chain: a, b. Fragment: transmembrane region, unp residues 536-573. Synonym: tyrosine-protein kinase receptor eph, epha1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: epha1. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

12 models

Authors:

M.L.Mayzel,E.V.Bocharov,A.S.Arseniev,M.V.Goncharuk

Key ref:

E.V.Bocharov et al. (2008). Spatial Structure and pH-dependent Conformational Diversity of Dimeric Transmembrane Domain of the Receptor Tyrosine Kinase EphA1. J Biol Chem, 283, 29385-29395. PubMed id: 18728013 DOI: 10.1074/jbc.M803089200

Date:

06-Mar-08 Release date: 09-Sep-08

Protein chains

P21709  (EPHA1_HUMAN) -  Ephrin type-A receptor 1 from Homo sapiens

Seq: 976 a.a.

Struc: 38 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1074/jbc.M803089200

J Biol Chem 283:29385-29395 (2008)

PubMed id: 18728013

Spatial Structure and pH-dependent Conformational Diversity of Dimeric Transmembrane Domain of the Receptor Tyrosine Kinase EphA1.

E.V.Bocharov, M.L.Mayzel, P.E.Volynsky, M.V.Goncharuk, Y.S.Ermolyuk, A.A.Schulga, E.O.Artemenko, R.G.Efremov, A.S.Arseniev.

ABSTRACT

Eph 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 alpha-helical bundle, region (544-569)(2), through the N-terminal glycine zipper motif A(550)X(3)G(554)X(3)G(558). Under acidic conditions, the N terminus of the transmembrane helix is stabilized by an N-capping box formed by the uncharged carboxyl group of Glu(547), whereas 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 utilizing seemingly the C-terminal GG4-like dimerization motif A(560)X(3)G(564). This can be interpreted as the ability of the EphA1 receptor to adjust its response to ligand binding according to extracellular pH. The dependence of the pK(a) value of Glu(547) 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 the Eph family, implying its possible physiological role as an "extracellular pH sensor," and can have relevant physiological implications.

Selected figure(s)

Figure 4.
Helix packing perturbations in the EphA1tm dimer caused by deprotonation of Glu^547 carboxyl group. A and B, ribbon diagrams of the NMR-derived spatial structures of the EphA1tm dimer before (A) and after (B) MD relaxation in explicit lipid bilayer. The dimer structures (superimposed on one subunit) obtained for EphA1tm embedded in the DMPC/DHPC bicelles at pH 4.3 and 6.3 are shown in light and dark gray, respectively. C and D, the EphA1tm helix packing interface after MD relaxation in explicit lipid bilayer. Hydrophobicity maps (on the left) for EphA1tm helix surface with contour isolines encircling hydrophobic regions with high values of molecular hydrophobicity potential are covered by areas of dark points indicating the N-terminal dimerization interface realized in the major right-handed dimer conformation at pH 4.3 (C) and pH 6.3 (D). A possible C-terminal dimerization interface implying a left-handed crossing of the EphA1tm TM helices is highlighted by dashed curved lines (D). The helix packing contact areas per EphA1tm residue averaged over the equilibrium part (last 2 ns) of restrained MD relaxation of the dimer structure are presented at the right of the maps. The spreads of the contact area are shown by bars. deg., degree.

Figure 5.
N-cap configurations of the EphA1tm helix depending on the ionization state of Glu^547 carboxyl group. Possible transient hydrogen bond connections in the N terminus of the TM helix observed during MD relaxation of the NMR-derived structures of the EphA1tm dimer embedded in the DMPC/DHPC bicelles at pH 4.3 (A) and 6.3 (B) are shown by dashed lines.

The above figures are reprinted from an Open Access publication published by the ASBMB: J Biol Chem (2008, 283, 29385-29395) copyright 2008.

Figures were selected by an automated process.