title: Cooperative assembly of Co-Smad4 MH1 with R-Smad1/3 MH1 on DNA: a molecular dynamics simulation study.
abstract: BACKGROUND
  Smads, the homologs of Sma and MAD proteins, play a key role in gene expression regulation in the transforming growth factor-β (TGF-β) signaling pathway. Recent experimental studies have revealed that Smad4/R-Smad heterodimers bound on DNA are energetically more favorable than homodimeric R-Smad/R-Smad complexes bound on DNA, which indicates that Smad4 might act as binding vehicle to cooperatively assemble with activated R-Smads on DNA in the nucleus. However, the details of interaction mechanism for cooperative recruitment of Smad4 protein to R-Smad proteins on DNA, and allosteric communication between the Smad4-DNA and R-Smad-DNA interfaces via DNA mediating are not yet clear so far.
  
  
  METHODS
  In the present work, we have constructed a series of Smadn+DNA+Smadn (n = 1, 3, 4) models and carried out molecular dynamics simulations, free energy calculations and DNA dynamics analysis for them to study the interaction properties of Smadn (n = 1, 3, 4) with DNA molecule.
  
  
  RESULTS
  The results revealed that the binding of Smad4 protein to DNA molecule facilitates energetically the formation of the heteromeric Smad4+DNA+Smad1/3 complex by increasing the affinity of Smad1/3 with DNA molecule. Further investigations through the residue/base motion correlation and DNA dynamics analyses predicted that the binding of Smad4 protein to DNA molecule in the heteromeric Smad4+DNA+Smad1/3 model induces an allosteric communication from the Smad4-DNA interface to Smad1/Smad3-DNA interface via DNA base-pair helical motions, surface conformation changes and new hydrogen bond formations. The present work theoretically explains the mechanism of cooperative recruitment of Smad4 protein to Smad1/3 protein via DNA-mediated indirect readout mode in the nucleus.
authors: College of Chemistry, Beijing Normal University, Beijing, People's Republic China.
authors: Guihong
authors: G
authors: Wang
authors: Chaoqun
authors: C
authors: Li
authors: Yan
authors: Y
authors: Wang
authors: Guangju
authors: G
authors: Chen
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry; D051379:Mice; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000737:chemistry*; D051898:Smad1 Protein / Q000737:chemistry*; D051901:Smad4 Protein / Q000737:chemistry*
chemical_list: D004268:DNA-Binding Proteins; D051896:Smad Proteins, Receptor-Regulated; D051898:Smad1 Protein; D051901:Smad4 Protein; D004247:DNA