Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex

Nat Struct Biol. 2002 Mar;9(3):203-8. doi: 10.1038/nsb766.

Abstract

Transforming growth factor-beta (TGF-beta) is the prototype of a large family of structurally related cytokines that play key roles in maintaining cellular homeostasis by signaling through two classes of functionally distinct Ser/Thr kinase receptors, designated as type I and type II. TGF-beta initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 A crystal structure of the extracellular ligand-binding domain of the human TGF-beta type II receptor (ecTbetaR2) in complex with human TGF-beta3. ecTbetaR2 interacts with homodimeric TGF-beta3 by binding identical finger segments at opposite ends of the growth factor. Relative to the canonical 'closed' conformation previously observed in ligand structures across the superfamily, ecTbetaR2-bound TGF-beta3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-beta3 binding shown by ecTbetaR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-beta binding to the type I receptor ectodomain (ecTbetaR1), suggests an assembly mechanism in which ecTbetaR1 and ecTbetaR2 bind at adjacent positions on the ligand surface and directly contact each other via protein--protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Protein Subunits
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry*
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Sequence Alignment
  • Structure-Activity Relationship
  • Transforming Growth Factor beta / chemistry*
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta3

Substances

  • Ligands
  • Protein Subunits
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta3
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II

Associated data

  • PDB/1KTZ