We will determine the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK lateral dimerization. The six receptors chosen for this study, ErbB1, ErbB2, ErbB3, FGFR1, FGFR2, and FGFR3, have been linked to human pathologies. The contributions of the different domains in these six RTKs to the dimerization free energies are currently unknown, mainly due to experimental challenges in the study of full-length RTKs, and membrane proteins in general. Here we will use a novel experimental approach, based on quantitative FRET, which yields dimerization thermodynamics in plasma membranes derived from mammalian cells. The work proposed here is the first step towards comprehensive characterization of the interplay between the different RTK domains in signaling. It will provide basic knowledge regarding the role of the different domains in the dimerization process, and thus aid in the development of highly specific therapeutics which can be used to treat cancers and growth disorders.
RTK domains and RTK dimerization thermodynamics Narrative Many pathologies are believed to occur due to disregulation of ligand-independent RTK dimerization. Here we will gain insight into this process by determining the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK dimerization. The proposed work will aid in the development of highly specific therapeutics that can be used to treat cancers and growth disorders.
|Sarabipour, Sarvenaz; King, Christopher; Hristova, Kalina (2014) Uninduced high-yield bacterial expression of fluorescent proteins. Anal Biochem 449:155-7|
|Placone, Jesse; He, Lijuan; Del Piccolo, Nuala et al. (2014) Strong dimerization of wild-type ErbB2/Neu transmembrane domain and the oncogenic Val664Glu mutant in mammalian plasma membranes. Biochim Biophys Acta 1838:2326-30|
|Bocharov, Eduard V; Lesovoy, Dmitry M; Goncharuk, Sergey A et al. (2013) Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies. Structure 21:2087-93|
|Sarabipour, Sarvenaz; Hristova, Kalina (2013) FGFR3 transmembrane domain interactions persist in the presence of its extracellular domain. Biophys J 105:165-71|
|Chen, Fenghao; Sarabipour, Sarvenaz; Hristova, Kalina (2013) Multiple consequences of a single amino acid pathogenic RTK mutation: the A391E mutation in FGFR3. PLoS One 8:e56521|
|Li, Edwin; Wimley, William C; Hristova, Kalina (2012) Transmembrane helix dimerization: beyond the search for sequence motifs. Biochim Biophys Acta 1818:183-93|
|He, Lijuan; Serrano, Christopher; Niphadkar, Nitish et al. (2012) Effect of the G375C and G346E achondroplasia mutations on FGFR3 activation. PLoS One 7:e34808|
|Wimley, William C; Hristova, Kalina (2011) Antimicrobial peptides: successes, challenges and unanswered questions. J Membr Biol 239:27-34|
|Hristova, Kalina; Wimley, William C (2011) A look at arginine in membranes. J Membr Biol 239:49-56|
|Chen, Fenghao; Degnin, Catherine; Laederich, Melanie et al. (2011) The A391E mutation enhances FGFR3 activation in the absence of ligand. Biochim Biophys Acta 1808:2045-50|
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