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HER2 Transmembrane Domain Dimerization Coupled with Self-Association of Membrane-Embedded Cytoplasmic Juxtamembrane

Pavel E Bragin1, Konstantin S Mineev2, Olga V Bocharova2

  • 1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya Street, Moscow 117997, Russian Federation; Lomonosov Moscow State University, Leninskie Gory, 1, Moscow 119991, Russian Federation.

Journal of Molecular Biology
|November 21, 2015
PubMed

Insights

Researchers discovered a new dimerization mode in the HER2 transmembrane domain. This alternative dimerization, observed in micelles, may inhibit receptor kinase activity, refining understanding of HER/ErbB signaling in cells and cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Signaling

Background:

  • Receptor tyrosine kinases, including the human epidermal growth factor receptor (HER or ErbB) family, are crucial for cellular processes and cancer.
  • HER/ErbB receptors signal by dimerizing after ligand binding, involving extracellular, transmembrane, and cytoplasmic domains.
  • Previous studies described HER2 transmembrane domain dimerization in lipid bicelles, linked to receptor activation.

Purpose of the Study:

  • To investigate alternative dimerization modes of the HER2 transmembrane domain.
  • To elucidate the role of the juxtamembrane region in HER2 receptor signaling.
  • To refine the molecular mechanism of signal propagation in HER/ErbB receptors.

Main Methods:

  • High-resolution Nuclear Magnetic Resonance (NMR) spectroscopy.
  • Utilizing a membrane-mimicking micellar environment.
  • Structural analysis of the HER2 transmembrane domain and juxtamembrane region.

Main Results:

  • Identified an alternative dimerization mode of the HER2 transmembrane domain in a micellar environment.
  • Observed self-association of the membrane-embedded cytoplasmic juxtamembrane region coupled with transmembrane dimerization.
  • This alternative dimerization appears to inhibit the receptor's kinase activity.

Conclusions:

  • The newly identified dimerization mode provides a mechanism for inhibiting HER2 kinase activity.
  • This finding expands the understanding of HER2 transmembrane domain interactions and their role in signal transduction.
  • Refines the molecular model of signal propagation from extracellular to cytoplasmic domains in HER/ErbB receptors.
Keywords:
alternative dimerization of transmembrane and cytoplasmic juxtamembrane domainscoupled protein–protein and protein–lipid interactionsheteronuclear NMR using membrane-mimicking micellar environmentinactive and active states of HER2 receptor tyrosine kinasestructure–function relationship

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