A structural basis for mutational inactivation of the tumour suppressor Smad4 Journal Article
| Authors: | Shi, Y.; Hata, A.; Lo, R. S.; Massagué, J.; Pavletich, N. P. |
| Article Title: | A structural basis for mutational inactivation of the tumour suppressor Smad4 |
| 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-β/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 Å 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. |
| Keywords: | gene mutation; dna-binding proteins; protein conformation; carboxy terminal sequence; protein assembly; gene expression regulation; tumor suppressor gene; gene activation; amino acid sequence; molecular sequence data; sequence homology, amino acid; gene disruption; escherichia coli; recombinant proteins; effector cell; models, molecular; crystallography, x-ray; trans-activators; oligomerization; genes, tumor suppressor; gene structure; smad4 protein; humans; priority journal; article |
| Journal Title: | Nature |
| Volume: | 388 |
| Issue: | 6637 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1997-07-03 |
| Start Page: | 87 |
| End Page: | 93 |
| Language: | English |
| DOI: | 10.1038/40431 |
| PUBMED: | 9214508 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
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