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 language | English (US) |
|---|---|
| Pages (from-to) | 152-155 |
| Number of pages | 4 |
| Journal | Protein Science |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2012 |
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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 journal › Article
}
TY - JOUR
T1 - The ErbB4 extracellular region retains a tethered-like conformation in the absence of the tether
AU - Liu, Ping
AU - Bouyain, Samuel
AU - Eigenbrot, Charles
AU - Leahy, Daniel J.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - Autoinhibition
KW - EGFR
KW - ErbB4
KW - Structure
UR - http://www.scopus.com/inward/record.url?scp=84455204129&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84455204129&partnerID=8YFLogxK
U2 - 10.1002/pro.753
DO - 10.1002/pro.753
M3 - Article
C2 - 22012915
AN - SCOPUS:84455204129
VL - 21
SP - 152
EP - 155
JO - Protein Science
JF - Protein Science
SN - 0961-8368
IS - 1
ER -