A Structural Basis for Mutational Inactivation of the Tumour Suppressor Smad4

Nature. 1997 Jul 3;388(6637):87-93. doi: 10.1038/40431.

Abstract

The Smad4/DPC4 tumour suppressor is inactivated in nearly half of pancreatic carcinomas and to a lesser extent in a variety of other cancers. Smad4/DPC4, and the related tumour suppressor Smad2, belong to the SMAD family of proteins that mediate signalling by the TGF-beta/activin/BMP-2/4 cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins, which are phosphorylated by the activated receptor, propagate the signal, in part, through homo- and hetero-oligomeric interactions. Smad4/DPC4 plays a central role as it is the shared hetero-oligomerization partner of the other SMADs. The conserved carboxy-terminal domains of SMADs are sufficient for inducing most of the ligand-specific effects, and are the primary targets of tumorigenic inactivation. We now describe the crystal structure of the C-terminal domain (CTD) of the Smad4/DPC4 tumour suppressor, determined at 2.5 A resolution. The structure reveals that the Smad4/DPC4 CTD forms a crystallographic trimer through a conserved protein-protein interface, to which the majority of the tumour-derived missense mutations map. These mutations disrupt homo-oligomerization in vitro and in vivo, indicating that the trimeric assembly of the Smad4/DPC4 CTD is critical for signalling and is disrupted by tumorigenic mutations.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • DNA-Binding Proteins*
  • Escherichia coli
  • Gene Expression Regulation*
  • Genes, Tumor Suppressor*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Sequence Homology, Amino Acid
  • Smad4 Protein
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / chemistry*
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism

Substances

  • DNA-Binding Proteins
  • Recombinant Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators

Associated data

  • PDB/UNKNOWN