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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 β-strand addition and coiled coils interactions between terminal α-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.

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Figure 1: Structure of the minimal Tfb2–Tfb5 complex.
Figure 2: Structural basis for group A trichotyodystrophy.
Figure 3: TTD-A mutations and deletion of the p8 (Tfb5)-interacting domain in p52 (Tfb2) affect TFIIH's NER but not transcription activity.

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Acknowledgements

We thank F. Coin and M. Zurita for fruitful discussions and D. Moras for strong support and advice. We thank V. Cura, A. Mitschler and R. Sanishvili for help with data collection and staff at the European Synchotron Facility (ESRF, ID14) and Advanced Photon Source (APS, GM/CA CAT, ANL, ID23) for use of synchrotron facilities. We acknowledge G. Zeder-Lutz (Bioacapt, ESBS) for SPR measurements, I. Kolb-Cheynel (IGBMC Baculovirus Facility) for protein production in insect cells and C. Brown for excellent technical assistance. This work was supported by funds from ANR-maladies rares contract ANR-05-MRAR-005-02, the Association de la Recherche sur le Cancer, the Ligue contre le Cancer and the European Commission as SPINE2-complexes contract no. LSHG-CT-2006-031220. D.E.K. was supported by EMBO-LTF.

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D.E.K., A.P. and J.-M.E. designed the research; D.E.K., M.V. and A.P. performed the experiments; D.E.K., J.C. and A.P. solved structures; D.E.K., J.C., J.-M.E. and A.P. wrote the manuscript.

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Correspondence to Arnaud Poterszman or Jean-Marc Egly.

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Supplementary Figures 1–4, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 397 kb)

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Kainov, D., Vitorino, M., Cavarelli, J. et al. Structural basis for group A trichothiodystrophy. Nat Struct Mol Biol 15, 980–984 (2008). https://doi.org/10.1038/nsmb.1478

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