The complete structure of the human TFIIH core complex

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Article and author information
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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.

The following data sets were generated

1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Cryo-EM map of the human TFIIH core complex at 3.7 Å
Electron Microscopy Data Bank, EMD-0452.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0452
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Refined coordinate model of the human TFIIH core complex at 3.7 Å
Protein Data Bank, 6NMI.

http://www.rcsb.org/structure/6NMI
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Cryo-EM map resulting from the classification of the dataset for presence of the MAT1 RING domain
Electron Microscopy Data Bank, EMD-0587.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0587
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Cryo-EM map resulting from the classification of the dataset for presence of the p62 BSD2 domain
Electron Microscopy Data Bank, EMD-0589.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0589
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Cryo-EM map resulting from the classification of the dataset for absence of the p62 BSD2 domain
Electron Microscopy Data Bank, EMD-0588.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0588
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Multibody-refined map for XPD-MAT1
Electron Microscopy Data Bank, EMD-0602.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0602
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Multibody-refined map for XPB-p8-p52 (clutch, CTD)
Electron Microscopy Data Bank, EMD-0603.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0603
1. Greber BJ
2. Toso DB
3. Fang J
4. Nogales E
(2019) Multibody-refined map for p44-p34-p62-p52 (N-terminal region)
Electron Microscopy Data Bank, EMD-0604.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-0604

Article and author information

Author details

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.
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.
Jie Fang

Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.