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Structural polymorphism of the PH domain in TFIIH
Masahiko Okuda1, Yoshifumi Nishimura1,2
1Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Bioscience Reports
|June 21, 2023
Summary
The pleckstrin homology (PH) domain of the general transcription factor TFIIH shows structural similarity to human PH domains, not budding yeast PH domains. This PH domain interacts with target proteins in diverse ways across different yeast and metazoan species.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- The general transcription factor TFIIH is crucial for transcription, DNA repair, and cell cycle regulation in eukaryotes.
- The pleckstrin homology (PH) domain within TFIIH subunits (like human p62 and yeast Tfb1) mediates recruitment to specific DNA sites.
- Fungal PH domains are structurally divergent, with only the Saccharomyces cerevisiae (budding yeast) PH domain structure previously known.
Purpose of the Study:
- To determine the structure of the PH domain from Schizosaccharomyces pombe (fission yeast) Tfb1 (spPH) using Nuclear Magnetic Resonance (NMR).
- To compare the structure and target-binding properties of spPH with known human (hPH) and budding yeast (scPH) domains.
- To elucidate the binding modes of spPH to its interacting partners, spTfa1 and spRhp41.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the 3D structure of the spPH domain.
- Bioinformatic analysis was employed to compare amino acid sequence identity and predict target-binding sites.
- Chemical shift perturbation experiments were conducted to identify binding interfaces between spPH and its target proteins.
Main Results:
- The spPH domain exhibits an architecture more closely related to the human PH domain (hPH) than to the budding yeast PH domain (scPH), despite higher sequence identity to scPH.
- Key residues for specific binding, identified in hPH, are present in spPH, suggesting conserved functional importance.
- spPH interacts with spTfa1 and spRhp41 via distinct binding modes on a similar but unique surface, differing from hPH and scPH interactions.
Conclusions:
- The PH domain of TFIIH displays structural and functional plasticity, with fission yeast PH domains showing closer resemblance to metazoan counterparts than to budding yeast.
- The polymorphic binding modes highlight the adaptability of TFIIH PH domains in interacting with diverse target proteins across different eukaryotic lineages.
- This study reveals novel insights into the evolutionary divergence and conserved functional elements of TFIIH PH domains in transcription and DNA repair.
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