1dd1
From Proteopedia
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CRYSTAL STRUCTURE ANALYSIS OF THE SMAD4 ACTIVE FRAGMENT
Contents |
Overview
BACKGROUND: Smad4 functions as a common mediator of transforming growth, factor beta (TGF-beta) signaling by forming complexes with the, phosphorylated state of pathway-restricted SMAD proteins that act in, specific signaling pathways to activate transcription. SMAD proteins, comprise two domains, the MH1 and MH2 domain, separated by a linker, region. The transcriptional activity and synergistic effect of Smad4, require a stretch of proline-rich sequence, the SMAD-activation domain, (SAD), located N-terminal of the MH2 domain. To understand how the SAD, contributes to Smad4 function, the crystal structure of a fragment, including the SAD and MH2 domain (S4AF) was determined. RESULTS: The, structure of the S4AF trimer reveals novel features important for Smad4, function. A Smad4-specific sequence insertion within the MH2 domain, interacts with the C-terminal tail to form a structural extension from the, core. This extension (the TOWER) contains a solvent-accessible, glutamine-rich helix. The SAD reinforces the TOWER and the structural core, through interactions; two residues involved in these interactions are, targets of tumorigenic mutation. The solvent-accessible proline residues, of the SAD are located on the same face as the glutamine-rich helix of the, TOWER, forming a potential transcription activation surface. A tandem, sulfate-ion-binding site was identified within the subunit interface, which may interact with the phosphorylated C-terminal sequence of, pathway-restricted SMAD proteins. CONCLUSIONS: The structure suggests that, the SAD provides transcriptional capability by reinforcing the structural, core and coordinating with the TOWER to present the proline-rich and, glutamine-rich surfaces for interaction with transcription partners. The, sulfate-ion-binding sites are potential 'receptors' for the phosphorylated, sequence of pathway-restricted SMAD proteins in forming a heteromeric, complex. The structure thus provides a new model that can be tested using, biochemical and cellular approaches.
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
1DD1 is a Single protein structure of sequence from Homo sapiens with SO4 as ligand. Full crystallographic information is available from OCA.
Reference
Crystal structure of a transcriptionally active Smad4 fragment., Qin B, Lam SS, Lin K, Structure. 1999 Dec 15;7(12):1493-503. PMID:10647180
Page seeded by OCA on Mon Nov 12 16:31:06 2007
