The Epithelial Biochemistry Laboratory

New Stuff

Epithelial Biochemistry Laboratory

New Stuff

Structure of a ligand-bound, dimerized fragment of the EGF receptor

Growth factors are a class of proteins that provide cells with information about their external environment and then respond appropriately. For example, part of the wound healing process involves platelets releasing a growth factor called platelet-derived growth factor. Cells at the wound site respond to this growth factor and proliferate as part of the wound healing process. As growth factors do not enter the cell, they exert their effects on cells by binding to the extracellular parts of growth factor receptors. The intracellular parts of the receptor then initiate signalling inside of the cell which eventually results in changes to the cell. For most growth factor receptors, ligand-induced oligomerization of the receptors and activation of tyrosine kinase enzyme domains forms part of the process.

The epidermal growth factor (EGF) receptor is one of the first discovered growth factor receptors. Despite extensive characterization of the receptor, much remains to be determined about its mechanism of action. Several members of the Epithelial laboratory have been part of a collaboration with members of the Walter and Eliza Hall Institute and the Health Sciences and Nutrition division of the CSIRO determined the structure of a substantial fragment of the extracellular domain of the EGF receptor together. One of its ligands, the transforming growth factor alpha (TGF-alpha), is also present in this structure.

Worm representation of TGF-alpha bound to fragments of the EGF receptor (residues 1-501). The TGF-alpha molecules are colored green and blue, and the EGF receptor fragments are colored yellow and red.

The mode of ligand binding explains many mutagenesis studies performed on EGF and the TGF-alpha. Most notably, the conserved residue Arg 42 forms a salt bridge with EGF receptor residue Glu 355 and the required residue Leu 47 resides in a hydrophobic pocket in the receptor. To form the dimer, a long loop from one receptor projects out and makes significant contact with the other receptor. This mode of interaction is suprising and contrasts with the structures of other growth factor-receptor complexes where bound growth factor makes contact with two receptor molecules. The modes of ligand binding and receptor dimerization were also observed in a structure of the EGF-bound EGF receptor extracellular domains that was solved by the group of Professor Yokoyama at RIKEN, Japan shortly after the solution of our structure.

Solution of the structure will stimulate a number of new experiments that will further examine the mechanism as to how ligand binding induces activation of the enzymatic tyrosine kinase domain of the EGF receptor in order for signalling inside of the cell.

Lab members involved in the research:

Publications:
Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha
Garrett TPJ, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu H-J, Walker F, Frenkel MJ, Hoyne PA, Jorissen RN, Nice EC, Burgess AW, Ward CW.
Cell. 110: 763-773 (2002). [Medline entry]

Identification of a determinant of epidermal growth factor receptor ligand-binding specificity using a truncated, high-affinity form of the ectodomain.
Elleman TC, Domagala T, McKern NM, Nerrie M, Lönnqvist B, Adams TE, Lewis J, Lovrecz GO, Hoyne PA, Richards KM, Howlett GJ, Rothacker J, Jorissen RN, Lou M, Garrett TPJ, Burgess AW, Nice EC, Ward CW.
Biochemistry 40:8930-8939 (2001). [Medline entry]