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.
|King, Christopher; Raicu, Valerica; Hristova, Kalina (2017) Understanding the FRET Signatures of Interacting Membrane Proteins. J Biol Chem 292:5291-5310|
|Singh, Deo R; Ahmed, Fozia; Paul, Michael D et al. (2017) The SAM domain inhibits EphA2 interactions in the plasma membrane. Biochim Biophys Acta 1864:31-38|
|Wiedman, Gregory; Kim, Sarah Y; Zapata-Mercado, Elmer et al. (2017) pH-Triggered, Macromolecule-Sized Poration of Lipid Bilayers by Synthetically Evolved Peptides. J Am Chem Soc 139:937-945|
|Singh, Deo R; Ahmed, Fozia; Sarabipour, Sarvenaz et al. (2017) Intracellular Domain Contacts Contribute to Ecadherin Constitutive Dimerization in the Plasma Membrane. J Mol Biol 429:2231-2245|
|Del Piccolo, Nuala; Sarabipour, Sarvenaz; Hristova, Kalina (2017) A New Method to Study Heterodimerization of Membrane Proteins and Its Application to Fibroblast Growth Factor Receptors. J Biol Chem 292:1288-1301|
|King, Christopher; Stoneman, Michael; Raicu, Valerica et al. (2016) Fully quantified spectral imaging reveals in vivo membrane protein interactions. Integr Biol (Camb) 8:216-29|
|Sarabipour, Sarvenaz; Ballmer-Hofer, Kurt; Hristova, Kalina (2016) VEGFR-2 conformational switch in response to ligand binding. Elife 5:e13876|
|Sarabipour, Sarvenaz; Hristova, Kalina (2016) Pathogenic Cysteine Removal Mutations in FGFR Extracellular Domains Stabilize Receptor Dimers and Perturb the TM Dimer Structure. J Mol Biol 428:3903-3910|
|Sarabipour, Sarvenaz; Hristova, Kalina (2016) Effect of the achondroplasia mutation on FGFR3 dimerization and FGFR3 structural response to fgf1 and fgf2: A quantitative FRET study in osmotically derived plasma membrane vesicles. Biochim Biophys Acta 1858:1436-42|
|Sarabipour, Sarvenaz; Hristova, Kalina (2016) Mechanism of FGF receptor dimerization and activation. Nat Commun 7:10262|
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