title: Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain.
abstract: Thanatos-associated [THAP] domain-containing apoptosis-associated protein 1 (THAP1) is a DNA-binding protein that has been recently associated with DYT6 dystonia, a hereditary movement disorder involving sustained, involuntary muscle contractions. A large number of dystonia-related mutations have been identified in THAP1 in diverse patient populations worldwide. Previous reports have suggested that THAP1 oligomerizes with itself via a C-terminal coiled-coil domain, raising the possibility that DYT6 mutations in this region might affect this interaction. In this study, we examined the ability of wild-type THAP1 to bind itself and the effects on this interaction of the following disease mutations: C54Y, F81L, ΔF132, T142A, I149T, Q154fs180X, and A166T. The results confirmed that wild-type THAP1 associated with itself and most of the DYT6 mutants tested, except for the Q154fs180X variant, which loses most of the coiled-coil domain because of a frameshift at position 154. However, deletion of C-terminal residues after position 166 produced a truncated variant of THAP1 that was able to bind the wild-type protein. The interaction of THAP1 with itself therefore required residues within a 13-amino acid region (aa 154-166) of the coiled-coil domain. Further inspection of this sequence revealed elements highly consistent with previous descriptions of leucine zippers, which serve as dimerization domains in other transcription factor families. Based on this similarity, a structural model was generated to predict how hydrophobic residues in this region may mediate dimerization. These observations offer additional insight into the role of the coiled-coil domain in THAP1, which may facilitate future analyses of DYT6 mutations in this region.
authors.affiliation: Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Cem
authors.initials: C
authors.lastname: Sengel
authors.forename: Sophie
authors.initials: S
authors.lastname: Gavarini
authors.forename: Nutan
authors.initials: N
authors.lastname: Sharma
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.forename: D Cristopher
authors.initials: DC
authors.lastname: Bragg
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics*; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000378:metabolism; D003198:Computer Simulation; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D019281:Dimerization; D004422:Dystonia Musculorum Deformans / Q000235:genetics* / Q000378:metabolism; D000939:Epitopes / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D011487:Protein Conformation; D014162:Transfection; D014178:Translocation, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D000939:Epitopes; D007202:Indicators and Reagents; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; C474080:THAP1 protein, human; D004247:DNA