Structure of the Extracellular Region of HER3 Reveals an Interdomain Tether

  title={Structure of the Extracellular Region of HER3 Reveals an Interdomain Tether},
  author={Hyun-soo Cho and Daniel J. Leahy},
  pages={1330 - 1333}
We have determined the 2.6 angstrom crystal structure of the entire extracellular region of human HER3 (ErbB3), a member of the epidermal growth factor receptor (EGFR) family. The structure consists of four domains with structural homology to domains found in the type I insulin-like growth factor receptor. The HER3 structure reveals a contact between domains II and IV that constrains the relative orientations of ligand-binding domains and provides a structural basis for understanding both… 

Structure-based view of epidermal growth factor receptor regulation.

  • K. Ferguson
  • Biology, Chemistry
    Annual review of biophysics
  • 2008
High-resolution X-ray crystal structures determined in the past six years dramatically influence our view of ligand-induced activation of the epidermal growth factor receptor (EGFR) family of

Rigidity of the extracellular part of HER2: Evidence from engineering subdomain interfaces and shared‐helix DARPin‐DARPin fusions

The rigidity of HER2 on the surface of tumor cells is demonstrated by employing two orthogonal approaches of protein engineering, which exclude, on live cells and in vitro, that significant proportions of Her2 deviate from the “open” conformation.

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

It is suggested that the tether conformation may have evolved to prevent crosstalk between different EGFR Homologs and thus allow diversification of EGFR and its homologs.

A structural perspective on the regulation of the epidermal growth factor receptor.

The epidermal growth factor receptor is a receptor tyrosine kinase that plays a critical role in the pathogenesis of many cancers, and its activation mechanism is reviewed here.

Molecular modeling of nearly full-length ErbB2 receptor.

Favorable dimerization interactions are predicted for the extracellular, transmembrane, and protein kinase domains in the model of a nearly full-length dimer of ErbB2, which may act in a coordinated fashion in Erb B2 homodimerization, and also in heterodimers of ErBB2 with other members of the ErbA family.



Epidermal growth factor binding induces a conformational change in the external domain of its receptor.

The ligand additions to the human EGF receptor showed differences in both the near‐ and far‐UV CD spectra, and were similar for each ligand used, suggesting similar conformational differences between uncomplexed and complexed receptor.

Noncontiguous regions in the extracellular domain of EGF receptor define ligand-binding specificity.

Analysis of the binding properties of novel chicken/human EGFR chimera to further delineate the contact sequences in domain III and to assess the role of other regions of EGFR for their contribution to the display of high-affinity EGF binding concludes that noncontiguous regions of the EGFR contribute additively to the binding of EGF.

The Single Transmembrane Domains of ErbB Receptors Self-associate in Cell Membranes*

A role for TM domain interactions in ErbB receptor function is suggested, possibly in stabilizing inactive ligand-independent receptor dimers that have been observed by several groups.

Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor

The structure of the first three domains of IGF-1R (L1–Cys-rich–L2) determined to 2.6 Å resolution shows how the IR subfamily might interact with their ligands.

Identification of a determinant of epidermal growth factor receptor ligand-binding specificity using a truncated, high-affinity form of the ectodomain.

Murine and human epidermal growth factor receptors (EGFRs) bind human EGF (hEGF), mouse EGF (mEGF), and human transforming growth factor alpha (hTGF-alpha) with high affinity despite the significant

Dimerization of the Extracellular Domain of the Receptor for Epidermal Growth Factor Containing the Membrane-spanning Segment in Response to Treatment with Epidermal Growth Factor*

A recombinant fragment of the human receptor for epidermal growth factor containing both its extracellular domain and its membrane-spanning segment, when dissolved with Triton X-100, was observed to dimerize in response to addition of EGF even at the lowest concentration that could be assayed, suggesting that interfaces between cytoplasmic domains of intact EGF receptor impart significant stabilization to the dimer of the enzyme.

Two EGF molecules contribute additively to stabilization of the EGFR dimer

The proposed model of EGF‐induced sEGFR dimerization suggests possible mechanisms for both ligand‐induced homo‐ and heterodimerization of the EGFR (or erbB) family of receptors.

Direct identification of residues of the epidermal growth factor receptor in close proximity to the amino terminus of bound epidermal growth factor.

We have recently developed a kinetically controlled, step-wise affinity cross-linking technique for specific, high-yield, covalent linkage of murine epidermal growth factor (mEGF) via its N terminus

Solution structure of murine epidermal growth factor determined by NMR spectroscopy and refined by energy minimization with restraints.

The atomic coordinates resulting from the present structure refinement are important data for understanding the structures of EGF-like proteins and for further detailed comparisons of these structures with mEGF.