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The transmembrane domain of the oncogenic mutant ErbB-2 receptor: a structure obtained from site-specific infrared

Andrew J Beevers1, Andreas Kukol

  • 1Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK.

Journal of Molecular Biology
|August 8, 2006
PubMed

Insights

Researchers determined the atomic structure of the oncogenic ErbB-2 transmembrane domain dimer. This structure reveals a right-handed alpha-helical bundle, crucial for understanding uncontrolled cell division in cancer.

Area of Science:

  • Biophysics
  • Structural Biology
  • Molecular Oncology

Background:

  • ErbB-2 (also known as HER2) is an epidermal growth factor receptor.
  • An oncogenic mutation (Val664Glu) in the rat neu gene's transmembrane domain causes ErbB-2 dimerization and uncontrolled cell proliferation, leading to tumor formation.

Purpose of the Study:

  • To determine the experimentally defined atomic structure of the mutant ErbB-2 transmembrane domain dimer.
  • To elucidate the structural basis of permanent dimerization and its role in oncogenesis.

Main Methods:

  • Site-specific infrared dichroism (SSID) using 13C18O-labeled transmembrane peptides.
  • Experimental determination of alpha-helical constraints and orientational data (helix tilt).
  • Conformational search combined with molecular dynamics simulations in a lipid bilayer.

Main Results:

  • The study derived the alpha-helical structure of the mutant transmembrane domain dimer.
  • SSID data indicated local helix tilt angles ranging from 28° to 22°.
  • An experimentally defined atomic structure revealed a right-handed alpha-helical bundle, contrasting with previous left-handed models. Key residues (Ile659, Val663, Leu667, Ile671, Val674, Leu679) form the dimerisation interface.
  • Spacious Glu664 residues interact with water, not directly with each other, facilitating tight helical packing.

Conclusions:

  • The determined right-handed helical bundle structure provides a precise atomic model for the ErbB-2 transmembrane domain dimer.
  • This structure clarifies the mechanism of permanent dimerization and offers insights into ErbB-2-driven oncogenesis.
  • Findings contrast with prior computational models and highlight the role of water in stabilizing the dimer interface.

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