Solution structure and self-association properties of the p8 TFIIH subunit responsible for trichothiodystrophy.
Trichothiodystrophy (TTD) is a rare hereditary multi-system disorder associated with defects in nucleotide excision repair (NER) and transcription as consequences of mutations in XPB, XPD and p8/TTD-A subunits of transcription factor IIH (TFIIH). Here, we report the solution structure of the p8/TTD-A protein, a small alpha/beta protein built around an antiparallel beta-sheet that forms a homodimer with an extended interface. In order to characterize the dimer interface, we have introduced a mutation at position 44, which destabilizes the dimeric form of the protein. We have shown that this mutation has no effect on the intrinsic ability of p8/TTD-A to stimulate NER in vitro, but affects the capacity of p8/TTD-A to restore TFIIH concentration in TTD-A fibroblasts. Point mutations found in TTD-A patients are discussed on the basis of the present structure.
Vitorino
Marc
M
Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
Coin
Frédéric
F
Zlobinskaya
Olga
O
Atkinson
R Andrew
RA
Moras
Dino
D
Egly
Jean-Marc
JM
Poterszman
Arnaud
A
Kieffer
Bruno
B
D000015:Abnormalities, Multiple / Q000378:metabolism*; D000595:Amino Acid Sequence; D002850:Chromatography, Gel; D004260:DNA Repair; D019281:Dimerization; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry*; D012996:Solutions; D013329:Structure-Activity Relationship; D051758:Transcription Factor TFIIH / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*
C512380:GTF2H5 protein, human; D021122:Protein Subunits; D012996:Solutions; D014157:Transcription Factors; D051758:Transcription Factor TFIIH