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Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor

Nature Structural & Molecular Biology volume 18, pages 984989 (2011) | Download Citation


To our knowledge, no structural study to date has characterized, in an intact receptor, the coupling of conformational change in extracellular domains through a single-pass transmembrane domain to conformational change in cytoplasmic domains. Here we examine such coupling, and its unexpected complexity, using nearly full-length epidermal growth factor receptor (EGFR) and negative-stain EM. The liganded, dimeric EGFR ectodomain can couple both to putatively active, asymmetrically associated kinase dimers and to putatively inactive, symmetrically associated kinase dimers and monomers. Inhibitors that stabilize the active or inactive conformation of the kinase active site, as well as mutations in the kinase dimer interface and a juxtamembrane phosphorylation site, shift the equilibrium among the three kinase association states. This coupling of one conformation of an activated receptor ectodomain to multiple kinase-domain arrangements reveals previously unanticipated complexity in transmembrane signaling and facilitates regulation of receptor function in the juxtamembrane and cytoplasmic environments.

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This work was supported by US National Institutes of Health grant HL-48675. L.-Z.M., C.L. and T.A.S. thank J. Kuriyan for hosting them in 2004–2005 when experiments that eventually led to this work were initiated.

Author information


  1. Immune Disease Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.

    • Li-Zhi Mi
    • , Chafen Lu
    •  & Timothy A Springer
  2. Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Zongli Li
    •  & Thomas Walz
  3. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.

    • Noritaka Nishida


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L.-Z.M. prepared constructs, designed and carried out experiments, and wrote the manuscript. C.L. prepared constructs, designed and carried out experiments, and discussed the writeup. N.N. performed early EM experiments. Z.L. trained N.N. and L.-Z.M., and maintained and supervised the EM facility. T.W. discussed and supervised EM experiments and strategy, wrote the manuscript, and helped respond to referees. T.A.S. designed the overall experimental approach, supervised experiments, wrote the manuscript and responded to referees.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Timothy A Springer.

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