Identification of a functional site on the type I TGF-beta receptor by mutational analysis of its ectodomain

FEBS Lett. 2002 Feb 27;513(2-3):147-52. doi: 10.1016/s0014-5793(01)03231-8.

Abstract

Six charged amino acid residues located in the ectodomain of the full-length type I transforming growth factor (TGF)-beta receptor were individually mutated to alanine. Mutation of residues D47, D98, K102 and E104 resulted in functionally impaired receptors as demonstrated by a marked decrease in ligand-dependent signaling and ligand internalization relative to the wild-type receptor. The other two mutants (K39A and K87A) exhibited wild-type-like activity. Molecular modeling indicates that the four functionally important residues are located on the convex face of the ectodomain structure. Since mutation of these four residues affects signaling and ligand internalization but not ligand binding, we propose that this functional site is an interacting site between type I and II receptors.

MeSH terms

  • Activin Receptors, Type I / chemistry
  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • DNA Mutational Analysis
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Serine-Threonine Kinases
  • Protein Structure, Tertiary
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Structure-Activity Relationship

Substances

  • Ligands
  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Tgfbr1 protein, rat