The complete structure of the human TFIIH core complex
- University of California, Berkeley, United States
- Howard Hughes Medical Institute, University of California, Berkeley, United States
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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Cryo-EM map of the human TFIIH core complex at 3.7 ÅElectron Microscopy Data Bank, EMD-0452.
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Refined coordinate model of the human TFIIH core complex at 3.7 ÅProtein Data Bank, 6NMI.
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Cryo-EM map resulting from the classification of the dataset for presence of the MAT1 RING domainElectron Microscopy Data Bank, EMD-0587.
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Cryo-EM map resulting from the classification of the dataset for presence of the p62 BSD2 domainElectron Microscopy Data Bank, EMD-0589.
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Cryo-EM map resulting from the classification of the dataset for absence of the p62 BSD2 domainElectron Microscopy Data Bank, EMD-0588.
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Multibody-refined map for XPD-MAT1Electron Microscopy Data Bank, EMD-0602.
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Multibody-refined map for XPB-p8-p52 (clutch, CTD)Electron Microscopy Data Bank, EMD-0603.
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Multibody-refined map for p44-p34-p62-p52 (N-terminal region)Electron Microscopy Data Bank, EMD-0604.
Article and author information
Author details
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
- Nikolaus Grigorieff, Janelia Research Campus, Howard Hughes Medical Institute, United States
Version history
- Received: December 28, 2018
- Accepted: March 3, 2019
- Accepted Manuscript published: March 12, 2019 (version 1)
- 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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The complete structure of the human TFIIH core complex
eLife 8:e44771.
https://doi.org/10.7554/eLife.44771
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