1YGS

CRYSTAL STRUCTURE OF THE SMAD4 TUMOR SUPPRESSOR C-TERMINAL DOMAIN

Summary for 1YGS

• Entry DOI: 10.2210/pdb1ygs/pdb
• Descriptor: SMAD4 (2 entities in total)
• Functional Keywords: smad4, tumor suppressor c-terminal domain, tgf-beta signal mediator, beta-sandwich scaffold with a three-helix bundle, tumour suppressor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q13485
• Total number of polymer chains: 1
• Total formula weight: 25511.09

Authors

Shi, Y.,Hata, A.,Lo, R.S.,Massague, J.,Pavletich, N.P. (deposition date: 1997-10-03, release date: 1998-07-08, Last modification date: 2024-02-14)

Primary citation

Shi, Y.,Hata, A.,Lo, R.S.,Massague, J.,Pavletich, N.P.
A structural basis for mutational inactivation of the tumour suppressor Smad4.
Nature, 388:87-93, 1997

PubMed 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.

PubMed: 9214508
DOI: 10.1038/40431

Experimental method

X-RAY DIFFRACTION (2.1 Å)