The ErbB4 extracellular region retains a tethered-like conformation in the absence of the tether

Ping Liu, Samuel Bouyain, Charles Eigenbrot, Daniel J. Leahy

Research output: Contribution to journalArticle

Abstract

The epidermal growth factor receptor (EGFR) and its homologs ErbB3 and ErbB4 adopt a tethered conformation in the absence of ligand in which an extended hairpin loop from domain II contacts the juxtamembrane region of domain IV and tethers the domain I/II pair to the domain III/ IV pair. By burying the hairpin loop, which is required for formation of active receptor dimers, the tether contact was thought to prevent constitutive activation of EGFR and its homologs. Aminoacid substitutions at key sites within the tether contact region fail to result in constitutively active receptors however. We report here the 2.5 Å crystal structure of the N-terminal three extracellular domains of ErbB4, which bind ligand but lack domain IV and thus the tether contact. This ErbB4 fragment nonetheless adopts a domain arrangement very similar to the arrangement adopted in the presence of the tether suggesting that regions in addition to the tether contribute to maintaining this conformation and inactivity in the absence of the tether contact. We suggest that the tether conformation may have evolved to prevent crosstalk between different EGFR homologs and thus allow diversification of EGFR and its homologs. Published by Wiley-Blackwell.

Original languageEnglish (US)
Pages (from-to)152-155
Number of pages4
JournalProtein Science
Volume21
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Epidermal Growth Factor Receptor
Conformations
Ligands
Crosstalk
Dimers
Substitution reactions
Crystal structure
Chemical activation

Keywords

  • Autoinhibition
  • EGFR
  • ErbB4
  • Structure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

The ErbB4 extracellular region retains a tethered-like conformation in the absence of the tether. / Liu, Ping; Bouyain, Samuel; Eigenbrot, Charles; Leahy, Daniel J.

In: Protein Science, Vol. 21, No. 1, 01.2012, p. 152-155.

Research output: Contribution to journalArticle

Liu, Ping ; Bouyain, Samuel ; Eigenbrot, Charles ; Leahy, Daniel J. / The ErbB4 extracellular region retains a tethered-like conformation in the absence of the tether. In: Protein Science. 2012 ; Vol. 21, No. 1. pp. 152-155.
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