UNDERSTANDING AND REDEFNING NEUREGULIN SPECIFICITY

Project: Research project

Project Details

Description

The highly affinity binding of human neuregulin to the ErbB-3
receptor will be used to analyze the receptor ligand interaction in
this family of EGF receptor (ErbB-1) related receptors which is
implicated in various forms of human cancer. I will use a combination
of computational sequence analysis, directed mutagenesis and phage
display selection to construct a function based map of the ligand-
receptor interface. This analysis will result in two libraries, each of
which represents ten randomized residues on one of the two putative
contact surfaces between neuregulin and its receptor. These libraries
will be used separately and in combination for the phage display
selection of neuregulin isoforms which show specific binding to the
ErbB-2 receptor that is highly homologous to ErbB-3. So far, no
natural ligand that binds specifically to ErbB-2 has been fully
characterized. This receptor is overexpressed on a number of
aggressive breast cancer cell lines. Selected ErbB-2-specific ligands
can serve as targeting vehicles for "magic bullets" aimed at ErbB-2
overexpressing breast cancer cells. The usefulness of selected ErbB-2
specific isoforms of neurogulin will be demonstrated through fusion
with the catalytic and translocation domains of diphtheria toxin, to
generate an ErbB-2 specific directed toxin. The sixty amino acid EGF
like domain of the neuregulin isoform heregulin beta, that will be
used as the starting point for mutagenesis, will also be crystallized
for structure determination. This structure will complement the
existing NMR structures of the corresponding domain in EGF and
neuregulin hrg-alpha as well as aid in the analysis of ligand receptor
interaction.
StatusFinished
Effective start/end date11/1/9710/31/00

Funding

  • National Institute of Allergy and Infectious Diseases: $40,936.00
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases

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