The Extracellular Region of ErbB4 Adopts a Tethered Conformation in the Absence of Ligand

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 42; pp. 15024 - 15029
• Main Authors: Samuel Bouyain, Patti A. Longo, Shiqing Li, Ferguson, Kathryn M., Leahy, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.10.2005; National Acad Sciences
• Subjects: Adult; ADULTS; Amino Acid Sequence; Amino acids; Binding sites; Biochemistry; Biological Sciences; CRYSTAL STRUCTURE; Crystallography, X-Ray; Dimerization; Enzymes; ErbB Receptors - chemistry; ErbB Receptors - metabolism; GROWTH FACTORS; Human growth; Humans; LIGANDS; MATERIALS SCIENCE; Models, Molecular; Molecular Sequence Data; Molecules; national synchrotron light source; NEOPLASMS; PHOSPHOTRANSFERASES; Protein Binding; Protein Conformation; Proteins; Receptor, ErbB-4; Receptors; Sequence Alignment; Surface plasmon resonance; TYROSINE; Yttrium
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0507591102

The human ErbB family of receptor tyrosine kinases comprises the epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2 Neu), ErbB3 (HER3), and ErbB4 (HER4). ErbBs play fundamental roles in cell growth and differentiation events in embryonic and adult tissues, and inappropriate ErbB activity has been implicated in several human cancers. We report here the 2.4 Å crystal structure of the extracellular region of human ErbB4 in the absence of ligand and show that it adopts a tethered conformation similar to inactive forms of ErbB1 and ErbB3. This structure completes the gallery of unliganded ErbB receptors and demonstrates that all human ligand-binding ErbBs adopt the autoinhibited conformation. We also show that the binding of neuregulin-1β to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-α to ErbB1. These results indicate an important role for ligand in determining pH-dependent binding and may explain different responses observed when the same ErbB receptor is stimulated by different ligands.