1. Structural Biology and Molecular Biophysics
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The complete structure of the human TFIIH core complex

  1. Basil J Greber
  2. Daniel B Toso
  3. Jie Fang
  4. Eva Nogales  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Howard Hughes Medical Institute, University of California, Berkeley, United States
Research Article
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Cite this article as: eLife 2019;8:e44771 doi: 10.7554/eLife.44771

Abstract

Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair. The TFIIH core complex is sufficient for its repair functions and harbors the XPB and XPD DNA-dependent ATPase/helicase subunits, which are affected by human disease mutations. Transcription initiation additionally requires the CdK activating kinase subcomplex. Previous structural work has provided only partial insight into the architecture of TFIIH and its interactions within transcription pre-initiation complexes. Here, we present the complete structure of the human TFIIH core complex, determined by phase-plate cryo-electron microscopy at 3.7 Å resolution. The structure uncovers the molecular basis of TFIIH assembly, revealing how the recruitment of XPB by p52 depends on a pseudo-symmetric dimer of homologous domains in these two proteins. The structure also suggests a function for p62 in the regulation of XPD, and allows the mapping of previously unresolved human disease mutations.

Data availability

The cryo-EM map of the human TFIIH core complex at 3.7 Å and the refined coordinate model have been deposited to the EMDB and PDB with accession codes EMD-0452 and PDB-6NMI, respectively. Additional cryo-EM maps resulting from the classification of the dataset for presence of the MAT1 RING domain and for the p62 BSD2 domain (both presence and absence) have been deposited to the EMDB with accession codes EMD-0587, EMD-0589, and EMD-0588, respectively. The multibody-refined maps for XPD-MAT1, XPB-p8-p52 (clutch, CTD), and p44-p34-p62-p52 (N-terminal region) have been deposited with accession codes EMD-0602, EMD-0603, and EMD-0604, respectively.

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Author details

  1. Basil J Greber

    California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel B Toso

    California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jie Fang

    Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eva Nogales

    California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, United States
    For correspondence
    enogales@lbl.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9816-3681

Funding

National Institute of General Medical Sciences (R01-GM63072)

  • Eva Nogales

Howard Hughes Medical Institute

  • Eva Nogales

Swiss National Science Foundation (Advanced PostDoc Mobility Fellowship P300PA_160983)

  • Basil J Greber

National Institute of General Medical Sciences (R35-GM127018)

  • Eva Nogales

National Institute of General Medical Sciences (P01-GM063210)

  • Eva Nogales

Swiss National Science Foundation (Advanced PostDoc Mobility Fellowship P300PA_174355)

  • Basil J Greber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nikolaus Grigorieff, Janelia Research Campus, Howard Hughes Medical Institute, United States

Publication history

  1. Received: December 28, 2018
  2. Accepted: March 3, 2019
  3. Accepted Manuscript published: March 12, 2019 (version 1)
  4. Version of Record published: March 18, 2019 (version 2)

Copyright

© 2019, Greber et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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