title: Transmembrane domain of EphA1 receptor forms dimers in membrane-like environment.
abstract: Eph receptor tyrosine kinases (RTKs) are activated by a ligand-mediated dimerization in the plasma membrane and subjected to clusterization at a high local density of receptors and their membrane-anchored ligands. Interactions between transmembrane domains (TMDs) were recognized to assist to the ligand-binding extracellular domains in the dimerization of some RTKs, whereas a functional role of Eph-receptor TMDs remains unknown. We have studied a propensity of EphA1-receptor TMDs (TMA1) to self-association in membrane-mimetic environment. Dimerization of TMA1 in SDS environment was revealed by SDS-PAGE and confirmed by FRET analysis of the fluorescently labeled peptide (Kd=7.2+/-0.4 microM at 1.5 mM SDS). TMA1 dimerization was also found in 1,2-dimyristoyl-sn-glycero-3-phosphocholine liposomes (DeltaG=-15.4+/-0.5 kJ/mol). Stability of TMA1 dimers is comparable to the reported earlier stability of TMD dimers of fibroblast growth factor receptor 3 and tenfold weaker than the stability of TMD dimers of glycophorin A possessing high propensity to dimerization. Our results suggest that EphA1-receptor TMD contribute to the dimerization-mediated receptor activation. An assumed role of the TMD interactions is the efficient signal transduction due to TMD-driving mutual orientation of kinase domains in dimers, while a relatively low force of the TMD interactions does not prevent a ligand-controlled regulation of the receptor dimerization.
authors.affiliation: Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, RAS, ul. Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
authors.forename: Elena O
authors.initials: EO
authors.lastname: Artemenko
authors.forename: Natalya S
authors.initials: NS
authors.lastname: Egorova
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Arseniev
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Feofanov
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008823:Micelles; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D036082:Receptor, EphA1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008081:Liposomes; D008823:Micelles; D010455:Peptides; D036082:Receptor, EphA1