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

Journal Article · Sat Jan 01 04:00:00 EST 2005 · Proc Natl Acad Sci USA

DOI:https://doi.org/10.1073/pnas.0507591102· OSTI ID:913697

Bouyain, S; Longo, P; Li, S; Ferguson, K; Leahy, D

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 Angstrom 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-1{beta} 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-{alpha} 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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 913697
• Report Number(s): BNL--78265-2007-JA
• Journal Information: Proc Natl Acad Sci USA, Journal Name: Proc Natl Acad Sci USA Vol. 102; ISSN 0027-8424; ISSN PNASA6
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ADULTS
CRYSTAL STRUCTURE
GROWTH FACTORS
LIGANDS
NEOPLASMS
PHOSPHOTRANSFERASES
TYROSINE
national synchrotron light source