Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment

Natalia Jura, Nicholas F. Endres, Kate Engel, Sebastian Deindl, Rahul Das, Meindert H. Lamers, David E. Wemmer, Xuewu Zhang, John Kuriyan

Research output: Contribution to journalArticle

333 Citations (Scopus)

Abstract

Signaling by the epidermal growth factor receptor requires an allosteric interaction between the kinase domains of two receptors, whereby one activates the other. We show that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. The C-terminal half of the juxtamembrane segment latches the activated kinase domain to the activator, and the N-terminal half of this segment further potentiates dimerization, most likely by forming an antiparallel helical dimer that engages the transmembrane helices of the activated receptor. Our data are consistent with a mechanism in which the extracellular domains block the intrinsic ability of the transmembrane and cytoplasmic domains to dimerize and activate, with ligand binding releasing this block. The formation of the activating juxtamembrane latch is prevented by the C-terminal tails in a structure of an inactive kinase domain dimer, suggesting how alternative dimers can prevent ligand-independent activation.

Original languageEnglish (US)
Pages (from-to)1293-1307
Number of pages15
JournalCell
Volume137
Issue number7
DOIs
StatePublished - Jun 26 2009

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Epidermal Growth Factor Receptor
Catalytic Domain
Phosphotransferases
Chemical activation
Dimers
Ligands
Dimerization

Keywords

  • CELLBIO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jura, N., Endres, N. F., Engel, K., Deindl, S., Das, R., Lamers, M. H., ... Kuriyan, J. (2009). Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment. Cell, 137(7), 1293-1307. https://doi.org/10.1016/j.cell.2009.04.025

Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment. / Jura, Natalia; Endres, Nicholas F.; Engel, Kate; Deindl, Sebastian; Das, Rahul; Lamers, Meindert H.; Wemmer, David E.; Zhang, Xuewu; Kuriyan, John.

In: Cell, Vol. 137, No. 7, 26.06.2009, p. 1293-1307.

Research output: Contribution to journalArticle

Jura, N, Endres, NF, Engel, K, Deindl, S, Das, R, Lamers, MH, Wemmer, DE, Zhang, X & Kuriyan, J 2009, 'Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment', Cell, vol. 137, no. 7, pp. 1293-1307. https://doi.org/10.1016/j.cell.2009.04.025
Jura N, Endres NF, Engel K, Deindl S, Das R, Lamers MH et al. Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment. Cell. 2009 Jun 26;137(7):1293-1307. https://doi.org/10.1016/j.cell.2009.04.025
Jura, Natalia ; Endres, Nicholas F. ; Engel, Kate ; Deindl, Sebastian ; Das, Rahul ; Lamers, Meindert H. ; Wemmer, David E. ; Zhang, Xuewu ; Kuriyan, John. / Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment. In: Cell. 2009 ; Vol. 137, No. 7. pp. 1293-1307.
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