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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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DNA Repair
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Humans
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Models, Molecular
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Multiprotein Complexes / chemistry
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Mutation
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Protein Interaction Domains and Motifs
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Saccharomyces cerevisiae Proteins / chemistry
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Transcription Factor TFIIH / chemistry
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Transcription Factor TFIIH / genetics
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Transcription Factor TFIIH / metabolism
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Transcription, Genetic
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Trichothiodystrophy Syndromes / classification
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Trichothiodystrophy Syndromes / genetics
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Trichothiodystrophy Syndromes / metabolism*
Substances
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Multiprotein Complexes
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Recombinant Proteins
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Saccharomyces cerevisiae Proteins
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Tfb2 protein, S cerevisiae
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Tfb5 protein, S cerevisiae
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Transcription Factor TFIIH