Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling

Mol Cell. 2001 Dec;8(6):1277-89. doi: 10.1016/s1097-2765(01)00421-x.

Abstract

Ligand-induced phosphorylation of the receptor-regulated Smads (R-Smads) is essential in the receptor Ser/Thr kinase-mediated TGF-beta signaling. The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues. The pSer binding surface on the MH2 domain, frequently targeted for inactivation in cancers, is highly conserved among the Co- and R-Smads. This finding, together with mutagenesis data, pinpoints a functional interface between Smad2 and Smad4. In addition, the pSer binding surface on the MH2 domain coincides with the surface on R-Smads that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations define a bifunctional role for the MH2 domain as a pSer-X-pSer binding module in receptor Ser/Thr kinase signaling pathways.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Neoplasms / genetics
  • Phosphorylation
  • Phosphoserine / metabolism*
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • Sequence Alignment
  • Signal Transduction / drug effects*
  • Smad2 Protein
  • Smad4 Protein
  • Structure-Activity Relationship
  • Trans-Activators / chemistry*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / pharmacology*

Substances

  • DNA-Binding Proteins
  • SMAD2 protein, human
  • SMAD4 protein, human
  • Smad2 Protein
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Phosphoserine
  • Protein-Serine-Threonine Kinases

Associated data

  • PDB/1KHX