title: Structural basis for group A trichothiodystrophy.
abstract: Patients with the rare neurodevelopmental repair syndrome known as group A trichothiodystrophy (TTD-A) carry mutations in the gene encoding the p8 subunit of the transcription and DNA repair factor TFIIH. Here we describe the crystal structure of a minimal complex between Tfb5, the yeast ortholog of p8, and the C-terminal domain of Tfb2, the yeast p52 subunit of TFIIH. The structure revealed that these two polypeptides adopt the same fold, forming a compact pseudosymmetric heterodimer via a beta-strand addition and coiled coils interactions between terminal alpha-helices. Furthermore, Tfb5 protects a hydrophobic surface in Tfb2 from solvent, providing a rationale for the influence of p8 in the stabilization of p52 and explaining why mutations that weaken p8-p52 interactions lead to a reduced intracellular TFIIH concentration and a defect in nucleotide-excision repair, a common feature of TTD cells.
authors.affiliation: lnstitut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, France.
authors.forename: Denis E
authors.initials: DE
authors.lastname: Kainov
authors.forename: Marc
authors.initials: M
authors.lastname: Vitorino
authors.forename: Jean
authors.initials: J
authors.lastname: Cavarelli
authors.forename: Arnaud
authors.initials: A
authors.lastname: Poterszman
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D018360:Crystallography, X-Ray; D004260:DNA Repair; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D054463:Trichothiodystrophy Syndromes / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C517875:Tfb2 protein, S cerevisiae; C517874:Tfb5 protein, S cerevisiae; D051758:Transcription Factor TFIIH