Donaldson, Logan2016-04-222016-04-222016-04-22http://hdl.handle.net/10315/31187Group E members of the SOX transcription factor family include SOX8, SOX9, and SOX10. Preceding the high mobility group (HMG) domain in each of these proteins is a thirty-eight amino acid region that supports the formation of dimers on promoters containing tandemly inverted sites. From a mutagenic scan of the dimerization region, the most essential amino acids were clustered on the hydrophobic face of a single, predicted amphipathic helix. Consistent with our hypothesis that the dimerization region directly contacts the HMG domain, a peptide corresponding to the dimerization region bound a preassembled HMG-DNA complex. Sequence conservation among Group E members served as a basis to identify two surface exposed amino acids in the HMG domain of SOX9 that were necessary for dimerization. These data were combined to make a molecular model that places the dimerization region of one SOX9 protein onto the HMG domain of another SOX9 protein situated at the opposing site of a tandem promoter. The model explains how variable spacing between binding sites and different DNA bending angles can be accommodated through the participation of an unstructured linker region between the dimerization-specific helix and the HMG domain. Furthermore, the model provides a basis to explain why the A76E mutation in the dimerization region of human SOX9 is responsible for campomelic dysplasia, a disease associated with major limb and reproductive defectsenCC0 1.0 UniversalCC0 1.0 UniversalMolecular modelProtein-DNA interactionMolecular modelProtein-DNA interactionImage, 3-Dhttp://www.plosone.orghttp://www.plos.org