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

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. Amino-acid 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.

SUBMITTER: Liu P

PROVIDER: S-EPMC3323790 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Liu Ping P Bouyain Samuel S Eigenbrot Charles C Leahy Daniel J DJ

Protein science : a publication of the Protein Society 20111114 1

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. Amino-acid substitutions at key ...[more]

PMID: 22012915

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Project description:The conformational stability of the ?-hairpin miniprotein, CLN025, a variant of chignolin in which the N- and C-terminal glycines are replaced by tyrosines, in various concentrations of guanidinium chloride (GdmCl) and urea was examined by molecular dynamics simulations and electronic circular dichroism (ECD) spectropolarimetry. The peptide maintains its ?-hairpin conformation in GdmCl and urea solutions. In GdmCl, Gly7 influences the turn to reduce the number of Asp3-Gly7 H-bonds and the Tyr1-Trp9 H-bond is lost. The structure of the peptide is less stable in 3 M GdmCl than in water or 6 M GdmCl, because the number of Asp3-Thr8 and Tyr1-Tyr10 H-bonds are reduced and the Tyr2 side chain moves away from the Pro4 and Trp9 side chains and toward the Tyr10 side chain. This reduces the number of Tyr2-Pro4 CH-? interactions and Tyr2-Trp9 and Tyr1-Tyr10 aromatic-aromatic (Ar-Ar) interactions and increases the number of Tyr2-Tyr10 Ar-Ar interactions. In 6 M GdmCl at 300 and 333 K, the number of Tyr1-Tyr10 and Asp3-Thr8 H-bonds increases, but fewer structures have Tyr2-Pro4 CH-? and Tyr1-Tyr10 and Tyr2-Trp9 Ar-Ar interactions. In urea, Gly7 is in a mixture of ?-turn and random meander structures and the number of Asp3-Thr6 and Tyr1-Tyr10 H-bonds are reduced as are the number of Tyr2-Pro4 CH-? interactions and Tyr1-Tyr10 and Tyr2-Trp9 Ar-Ar interactions. In 4 M urea, a shorter turn places Gly7 into the ?-sheet region and Tyr10 is pushed out into the solvent. In 8 M urea, the number of Asp3-Glu5 H-bonds is increased and the ?-sheet is lost, but the electrostatic interaction between the charged termini is restored and a cation-? interaction between the indolyl ring of Trp9 and the positively charged N-terminus is formed. In 8 M urea at 333 K, the ?-hairpin conformation is almost lost. The structure of CLN025 is stable, because the weakly polar interactions and H-bonds maintain the ?-hairpin conformation in the various environments. CLN025 should not be considered a miniprotein, because it lacks a well-defined tertiary structure, it is resistant to denaturation, it does not have an increased heat capacity near its melting temperature, and the structures near and above the melting temperature retain a ?-hairpin conformation.

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

Publications

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

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