title: A dimerization hierarchy in the transmembrane domains of the HER receptor family.
abstract: Bitopic membrane proteins offer an opportunity for studying transmembrane domain interactions without the structural complexity inherent to multitopic integral membrane proteins. To date, only homomeric associations have been extensively studied quantitatively. Here we propose to assess the thermodynamics of heteromeric associations, which opens the way to investigating specificity and selectivity. A very interesting system of biological relevance with single transmembrane domains possibly involved in interactions with different partners is the EGFR receptor family. The four members, all tyrosine kinase receptors, are involved in an interaction network that potentially leads to a complete set of homo- and heterodimers, ideally suited to such a study. Furthermore, the transmembrane domains of these receptors have been previously implicated in their function in the past by mutations in the transmembrane domain leading to constitutive activation. We demonstrate, using a fluorescence-based measurement of interaction energies, a hierarchy of transmembrane domain interactions ranging from a noninteractive pair to strong dimerization. We propose a structural model based on the crystal structure of the EGFR dimer, to show how the dimeric structure favors these interactions. The correlation we observe between transmembrane domain and whole receptor interaction hierarchies opens a new perspective, suggesting a role for transmembrane receptor domains in the modulation of receptor signaling.
authors.affiliation: Unité Propre de Recherche-9027 Laboratoire d'Ingénierie des Systèmes Macromoléculaires, Institut de Biologie Structurale et Microbiologie, Centre National de la Recherche Scientifique, Marseille, France. duneau@ibsm.cnrs-mrs.fr
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Duneau
authors.forename: Attila P
authors.initials: AP
authors.lastname: Vegh
authors.forename: James N
authors.initials: JN
authors.lastname: Sturgis
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D066246:ErbB Receptors / Q000737:chemistry*; D005453:Fluorescence; D005456:Fluorescent Dyes; D005960:Glucosides; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011721:Pyrenes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry*; D020893:Receptor, ErbB-3 / Q000737:chemistry*; D066247:Receptor, ErbB-4; D013816:Thermodynamics
chemical_list: D066246:ErbB Receptors; D005456:Fluorescent Dyes; D005960:Glucosides; D010455:Peptides; D011721:Pyrenes; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C081853:2',4'-dinitrophenyl-2-deoxy-2-fluorocellobioside; C002218:1-pyrenebutyrate