We are interested in the stereochemical details of molecular interactions in signal transduction pathways, in particular those emanating from the stimulation of cell surface receptors by growth factors. Recent work has led to the proposal of a novel mechanism for the growth factor activation of one of the receptors we study, the epidermal growth factor receptor (EGFR). Using X-ray crystallography combined with a variety of biophysical and biochemical approaches, we are addressing the implications of this model on activation and inhibition of EGFR and other members of this receptor family. It is well established that dysregulation of EGFR, and of other members of this family, is linked to many cancers. Several EGFR targeted therapies are in use in the clinic and many more are in advanced stages of clinical trials. We have determined the X-ray crystal structures of the Fab fragments from three therapeutically relevant antibody drugs (from cetuximab/Erbitux, IMC-11F8, and matuzumab) in complex with the extracellular region of EGFR and have uncovered two distinct mechanisms used to prevent ligand-induced EGFR dimerization and activation. Structure-based models for EGFR activation suggest additional mechanisms that could also be of therapeutic value, and we are trying to exploit these with new antibody-based and other small molecules.
A second, developing, direction of the laboratory involves biophysical and structural studies of protein-protein interactions that control several events in intracellular vesicle trafficking pathways and endocytosis. In a collaboration with Christopher Burd (UPenn) we have gained an appreciation that the yeast protein Vps74p is required for proper localization of a subset of Golgi enzymes, and does this, at least in part, through direct interaction with the cytosolic tails of these enzymes. Vps74p forms a tetramer in crystals, and under certain solution conditions, and this tetramer is important for Vps74p function. We are investigating the molecular basis and regulation of Vps74p tetramer formation, which we hope will provide insights into the workings of the Golgi localization machinery.
Wood, C.S., Schmitz, K.R., Bessman, N.J., Thanuja Gangi Setty, T., Ferguson, K.M., and Burd, C.G.: PtdIns4P recognition by Vps74/GOLPH3 links PtdIns 4-kinase signaling to retrograde Golgi trafficking. J. Cell Biol. 187(7): 967-975, Dec. 2009.
Schmitz, K.R. and Ferguson, K.M.: Interaction of antibodies with ErbB receptor extracellular regions. Exp. Cell Res. 315(4): 659-670, Feb. 2009.
Schmitz, K.R., Liu, J., Li, S., Setty, T.G., Wood, C S., Burd, C.G. & Ferguson, K.M.: Golgi localization of glycosyltransferases requires a Vps74p oligomer. Dev. Cell 14(4): 523-534, Apr. 2008.
Lin, C., Huoh, Y., Schmitz, K.R., Jensen, L.E., & Ferguson, K.M.: Pellino proteins contain a cryptic FHA domain that mediates interaction with phosphorylated IRAK1. Structure 16(12): 1806-1816, Dec. 2008.
Schmiedel, J., Blaukat, A., Li, S., Knochel, T. & Ferguson, K.M.: Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization. Cancer Cell 13(4): 365-373, Apr. 2008.
Li, S., Kussie, P. & Ferguson, K.M.: Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure 16(2): 216-227, Feb. 2008.
Ferguson, K.M.: Structure-based view of epidermal growth factor receptor regulation. Ann. Rev. Biophys. 37: 353-373, Jun. 2008.
Li, S., Schmitz, K.R., Jeffrey, P.D., Wiltzius, J.J., Kussie, P. & Ferguson, K.M.
: Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7(4): 301-311, Apr. 2005.
Dawson, J.P., Berger, M.B., Lin, C.C., Schlessinger, J., Lemmon, M.A. & Ferguson, K.M.: Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol. Cell. Biol. 25(17): 7734-7742, Sep. 2005.
Ferguson, K.M., Berger, M.B., Mendrola, J.M., Cho, H.S., Leahy, D.J. & Lemmon, M. A.: EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11(2): 507-517, Feb. 2003.
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Last updated: 06/14/2013
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