Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein.
The neu proto-oncogene may be converted into a dominantly transforming oncogene by a single point mutation. Substitution of a valine residue at position 664 in the transmembrane region with glutamic acid activates the tyrosine kinase of the molecule and is associated with increased receptor dimerization. Previously we have proposed a model in which the glutamic acid side chain stabilizes receptor dimerization by hydrogen bonding. Other models have been proposed in which the mutation leads to a conformational change in the transmembrane region mimicking that assumed to occur following binding of a natural ligand. Synthetic peptides representing part of the transmembrane region were prepared. Some residues were replaced with serine in order to improve peptide solubility to allow purification and analysis. Both the peptides containing valine and glutamic acid dissolved in water and in an artificial lipid monolayer. The structures of the peptides were determined by NMR spectroscopy to be alpha-helical. No significant difference in conformation was observed between the two peptides. This result does not support the model proposing a conformational change. The receptor structures determined experimentally do allow alternative models involving receptor transmembrane region packing.
ICRF Oncology Group, Hammersmith Hospital, London, UK.
W J
WJ
Gullick
A C
AC
Bottomley
F J
FJ
Lofts
D G
DG
Doak
D
D
Mulvey
R
R
Newman
M J
MJ
Crumpton
M J
MJ
Sternberg
I D
ID
Campbell
D000595:Amino Acid Sequence; D000818:Animals; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D015513:Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases
D066246:ErbB Receptors; D008565:Membrane Proteins; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases