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Crystal structure of the Dachshund-homology domain of human SnoN

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PDB Code 3EQ5 Target Class Signalling proteins Target SKIL Alias SKIL, SNO, SnoA, SnoN Disease Area/Function cancer Date Deposited Sep 30 2008 Authors L.TRESAUGUES, M.WISNIEWSKA, J.ANDERSSON, C.H.ARROWSMITH, H.BERGLUND, C.BOUNTRA, R.COLLINS, L.G.DAHLGREN, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, A.JOHANSSON, I.JOHANSSON, T.KARLBERG, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, T.NYMAN, K.OLESEN, C.PERSSON, J.SAGEMARK, H.SCHUELER, A.G.THORSELL, S.VAN DER BERG, M.WELIN, M.WIKSTROM, J.WEIGELT, P.NORDLUND.

About this structure

Members of the TGF-β family of extracellular growth factors regulate cell proliferation, recognition, differentiation, apoptosis, and developmental fate in metazoans (1). One effect of the TGF-β proteins is to inhibit cell proliferation. Loss of cell responsiveness to TGF-β is thought to contribute to the pathogenesis of several epithelial tumors.

TGF-β ligands act by forming an activated heteromeric complex with specific transmembrane TGF-β serine/threonine receptors. The activated receptor catalyzes the phosphorylation of receptor-regulated Smad proteins (R-Smads) (2). Phosphorylated R-Smads then associate with the common partner Smad4 (co-Smad4). The thus formed Smad complex accumulates in the nucleus, where it binds smad-binding elements within promoters of TGF-β responsive genes to regulate their transcription, either by activation or repression, thereby affecting TGF-β dependent cellular responses. Additional transcriptional regulators modulate the ability of Smad protins to control the expression of TGF-β-responsive genes. One such regulator, the Smad-interacting ski-like protein (SKIL, or SnoN) has emerged as an important regulator of the TGF-β signaling pathway. SKIL is a member of the ski/sno/dac gene family, which share two regions of high homology. One referred to as the Dachshund homology domain, and a SAND domain. SAND domains are DNA binding domains found in a number of chromatin remodeling proteins. But in SKI and SKILA the DNA binding is absent and instead the SAND domain here interacts with Smads and other regulatory proteins.

Here, the structure of the Dachshund homology domain of SKIL is presented. The structure was solved to a resolution of 2.45 Å (Rfree=27.3%) by molecular replacement using the coordinates of the Dachshund-homology domain of human SKI (PDB-code : 1SBX) (3). The asymmetric unit (space-group C2) is composed of 12 monomers which are packed as a trimer of tetramers. This organization seems to be purely due to crystal packing as revealed by both gel-filtration profile and results from PISA server (4).This domain of SKIL adopts the fold described previously in the structure of the N-terminal domain of Dachshund (5). It consists in a four-stranded anti-parallel β-sheet flanked by three α-helices on one side and one on the other side. The 12 monomers are similar with the exception of helix α2 and the loop connecting α3 to β4 which are responsible for the overall rmsd value of 1.5 Å during superimposition of chain I and C for 94 superimposed residues. Superposition of SKIL and the Dachshund-homology domain of human SKI led to an rmsd of 0.74 Å for 96 superimposed residues in the case of monomer C and 1.30 Å for 84 superimposed residues in the case of monomer F. The increased rmsd value is mainly due to the same regions as described previously. The non-conserved residues between these two proteins are solvent exposed, a feature that could attribute to them a fundamental role during protein-protein interactions.

References

  1. Massagué, J. (1998). TGF-β-signal transduction. Annu. Rev. Biochem. 67, 753-791.
  2. Heldin,CH, Miyazomo, K. and ten Dijke, P. (1997) TGF-β signaling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-471
  3. Wilson JJ, Malakhova M, Zhang R, Joachimiak A and Hegde RS. Crystal structure of the dachshund homology domain of human SKI (2004) Structure 12(5): p. 785-92.
  4. Krissinel E and Henrick K. Inference of macromolecular assemblies from crystalline state (2007) J Mol Biol,. 372(3): p. 774-97.
  5. Kim SS, Zhang RG, Braunstein SE, Joachimiak A, Cvekl A and Hegde RS. Structure of the retinal determination protein Dachshund reveals a DNA binding motif (2002) Structure 10(6): p. 787-95.