1ygs
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The Smad4/DPC4 tumour suppressor is inactivated in nearly half of | + | 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== | ==Disease== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Hata, A.]] | [[Category: Hata, A.]] | ||
| - | [[Category: Lo, R | + | [[Category: Lo, R S.]] |
[[Category: Massague, J.]] | [[Category: Massague, J.]] | ||
| - | [[Category: Pavletich, N | + | [[Category: Pavletich, N P.]] |
[[Category: Shi, Y.]] | [[Category: Shi, Y.]] | ||
[[Category: beta-sandwich scaffold with a three-helix bundle]] | [[Category: beta-sandwich scaffold with a three-helix bundle]] | ||
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[[Category: tumor suppressor c-terminal domain]] | [[Category: tumor suppressor c-terminal domain]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:05:12 2008'' |
Revision as of 14:05, 21 February 2008
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CRYSTAL STRUCTURE OF THE SMAD4 TUMOR SUPPRESSOR C-TERMINAL DOMAIN
Contents |
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
Page seeded by OCA on Thu Feb 21 16:05:12 2008
