title: SnoN Stabilizes the SMAD3/SMAD4 Protein Complex.
abstract: TGF-β signaling regulates cellular processes such as proliferation, differentiation and apoptosis through activation of SMAD transcription factors that are in turn modulated by members of the Ski-SnoN family. In this process, Ski has been shown to negatively modulate TGF-β signaling by disrupting active R-SMAD/Co-SMAD heteromers. Here, we show that the related regulator SnoN forms a stable complex with the R-SMAD (SMAD3) and the Co-SMAD (SMAD4). To rationalize this stabilization at the molecular level, we determined the crystal structure of a complex between the SAND domain of SnoN and the MH2-domain of SMAD4. This structure shows a binding mode that is compatible with simultaneous coordination of R-SMADs. Our results show that SnoN, and SMAD heteromers can form a joint structural core for the binding of other transcription modulators. The results are of fundamental importance for our understanding of the molecular mechanisms behind the modulation of TGF-β signaling.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Walldén
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Nyman
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.|Röntgen-Ångström-Cluster, Karolinska Institutet Outstation, Centre for Structural Systems Biology, DESY-Campus, 22603 Hamburg, Germany.|European Molecular Biology Laboratory, Hamburg Unit, 22603 Hamburg, Germany.
authors.forename: B Martin
authors.initials: BM
authors.lastname: Hällberg
mesh_terms: D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein