1ygs

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spinqualitylabelsall models 1ygs, resolution 2.1Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF THE SMAD4 TUMOR SUPPRESSOR C-TERMINAL DOMAIN

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome OMIM:[600993], Pancreatic cancer OMIM:[600993], Polyposis, juvenile intestinal OMIM:[600993]

About this Structure

1YGS is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

A structural basis for mutational inactivation of the tumour suppressor Smad4., Shi Y, Hata A, Lo RS, Massague J, Pavletich NP, Nature. 1997 Jul 3;388(6637):87-93. PMID:9214508

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