Structural Mechanism of Smad4 Recognition by the Nuclear Oncoprotein Ski: Insights on Ski-mediated Repression of TGF-beta Signaling

Cell. 2002 Nov 1;111(3):357-67. doi: 10.1016/s0092-8674(02)01006-1.

Abstract

The Ski family of nuclear oncoproteins represses TGF-beta signaling through interactions with the Smad proteins. The crystal structure of the Smad4 binding domain of human c-Ski in complex with the MH2 domain of Smad4 reveals specific recognition of the Smad4 L3 loop region by a highly conserved interaction loop (I loop) from Ski. The Ski binding surface on Smad4 significantly overlaps with that required for binding of the R-Smads. Indeed, Ski disrupts the formation of a functional complex between the Co- and R-Smads, explaining how it could lead to repression of TGF-beta, activin, and BMP responses. Intriguingly, the structure of the Ski fragment, stabilized by a bound zinc atom, resembles the SAND domain, in which the corresponding I loop is responsible for DNA binding.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Cell Line, Transformed
  • DNA-Binding Proteins / chemistry*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis
  • Nuclear Proteins / chemistry*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry*
  • Signal Transduction*
  • Smad4 Protein
  • Trans-Activators / chemistry*
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • SKI protein, human

Associated data

  • PDB/1MR1