SAXS structure of VEGF and VEGFR complexesThe focus of our research is transmembrane signaling by receptor tyrosine kinases. We investigate Vascular Endothelial Growth Factors (VEGFs), which regulate blood and lymphatic vessel formation in angiogenesis and vasculogenesis. VEGF plays an important role in many diseases such as macular degeneration of the eye, arthritis, or in tumor growth and metastasis. We study the molecular mechanisms regulating VEGF receptor activity and develop molecular tools to interfere with receptor activation. We determined the structural changes induced in the extracellular receptor domain upon ligand binding by electron microscopy and small angle solution X-ray scattering. We also studied ligand binding to VEGF receptors by X-ray crystallography and solved the stuctures of complexes between VEGF-A, -C, and -E with the ligand binding domain (Ig-domains D2 and D3) of the receptor. In a second project we investigate how ligand-mediated receptor dimerization, and the resulting structural changes in the extracellular domain, instigate transmembrane signaling and promotie the activation of the intracellular kinase domain. To this end we generated a series of predimerized kinase constructs carrying dimerization-promoting transmembrane domains. The results show that distinct orientation of receptor dimers is required for kinase activation. Here our goal is to obtain high resolution structural information on the intracellular receptor kinase in the active and the inactive conformation. Finally, we studied the function of the different intracellular kinase subdomains in receptor activation and found that both the carboxyterminal as well as the kinase insert domain have a regulatory function in receptor activation.
High resolution crystallographic data for individual receptor subdomains will be combined with low resolution structures of the entire receptor obtained by electron microscopy and X-ray solution scattering to develop a functional model for VEGF receptor activation.
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Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation
Manni S, Mineev KS, Usmanova D, Lyukmanova EN, Shulepko MA, Kirpichnikov MP, Winter J, Matkovic M, Deupi X, Arseniev AS, and Ballmer-Hofer K
Structure 2014 Epub ahead of print http://dx.doi.org/10.1016/j.str.2014.05.010
Functional and structural characterization of the kinase insert and the carboxy terminal domain in VEGF receptor 2 activation
Manni Si, Kisko K, Schleier T, Missimer J, Ballmer-Hofer K.
FASEB J. 2014 DOI: 10.1096/fj.14-256206
Targeting extracellular domains D4 and D7 of vascular endothelial growth factor receptor 2 reveals allosteric receptor regulatory sites
Hyde CA, Giese A, Stuttfeld E, Abram Saliba J, Villemagne D, Schleier T, Binz HK and Ballmer-Hofer K.
Mol Cell Biol. 2012 Oct;32(19):3802-13