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Solution and solid state conformation of the human EGF receptor transmembrane region
A C Rigby1, C W Grant, G S Shaw
1Department of Biochemistry and McLaughlin Macromolecular Structure Facility, The University of Western Ontario, London, Ontario, Canada.
Biochimica Et Biophysica Acta
|June 19, 1998
Summary
Structural studies reveal the human epidermal growth factor receptor (hEGFR) transmembrane region forms an alpha-helix. This helix may extend into the cytosolic region, near a key phosphorylation site.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Cell Biology
Background:
- The epidermal growth factor receptor (EGFR) is a critical cell surface receptor tyrosine kinase.
- EGFR signaling is initiated by epidermal growth factor binding, leading to intracellular phosphorylation.
- The transmembrane domain is the sole communication link between extracellular and intracellular EGFR domains.
Purpose of the Study:
- To determine the structure of the human EGFR transmembrane region.
- To investigate the secondary structure and membrane interactions of a synthetic EGFR transmembrane peptide (hEGFRp).
Main Methods:
- Two-dimensional and 2H wideline NMR spectroscopy
- Circular dichroism (CD) spectroscopy
- Solid-state 2H NMR studies in lipid bilayers
Main Results:
- In aqueous solution, hEGFRp showed no regular secondary structure and formed oligomers.
- In trifluoroethanol (TFE), hEGFRp adopted a monomeric, structured form.
- NMR analysis identified an alpha-helix between residues M626 and R647 in hEGFRp.
- Solid-state NMR confirmed helical structure and axial symmetry within lipid bilayers.
- The helical region extended further than predicted, including charged residues on the cytosolic side.
Conclusions:
- The transmembrane region of EGFR forms an alpha-helix.
- This alpha-helical region may extend into the cytosolic domain near residue T654, an important phosphorylation site.
- These findings provide novel insights into EGFR structure and signaling mechanisms.