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A model for polyomavirus helicase activity derived in part from the AlphaFold2 structure of SV40 T-antigen.
- Source :
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Journal of virology [J Virol] 2024 Oct 22; Vol. 98 (10), pp. e0111924. Date of Electronic Publication: 2024 Sep 23. - Publication Year :
- 2024
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Abstract
- The mechanism used by polyomavirus and other viral SF3 helicases to unwind DNA at replication forks remains unknown. Using AlphaFold2, we have determined the structure of a representative SF3 helicase, the SV40 T-antigen (T-ag). This model has been analyzed in terms of the features of T-ag required for helicase activity, particularly the proximity of the T-ag origin binding domain (OBD) to the replication fork and the distribution of basic residues on the surface of the OBD that are known to play roles in DNA unwinding. These and related studies provide additional evidence that the T-ag OBDs have a role in the unwinding of DNA at the replication fork. Nuclear magnetic resonance and modeling experiments also indicate that protonated histidines on the surface of the T-ag OBD play an important role in the unwinding process, and additional modeling studies indicate that protonated histidines are essential in other SF3 and SF6 helicases. Finally, a model for T-ag's helicase activity is presented, which is a variant of the "rope climber." According to this model, the hands are the N-terminal OBD domains that interact with the replication fork, while the C-terminal helicase domains contain the feet that bind to single-stranded DNA.<br />Importance: Enzymes termed helicases are essential for the replication of DNA tumor viruses. Unfortunately, much remains to be determined about this class of enzymes, including their structures and the mechanism(s) they employ to unwind DNA. Herein, we present the full-length structure of a model helicase encoded by a DNA tumor virus. Moreover, this AI-based structure has been analyzed in terms of its basic functional properties, such as the orientation of the helicase at replication forks and the relative locations of the amino acid residues that are critical for helicase activity. Obtaining this information is important because it permits proposals regarding how DNA is routed through these model helicases. Also presented is structural evidence that the conclusions drawn from our detailed analyses of one model helicase, encoded by one class of tumor viruses, are likely to apply to other viral and eukaryotic helicases.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- DNA Replication
DNA, Viral metabolism
Antigens, Polyomavirus Transforming metabolism
Antigens, Polyomavirus Transforming chemistry
Protein Conformation
DNA Helicases metabolism
DNA Helicases chemistry
Models, Molecular
Antigens, Viral, Tumor metabolism
Antigens, Viral, Tumor chemistry
Simian virus 40
Polyomavirus
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 98
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 39311578
- Full Text :
- https://doi.org/10.1128/jvi.01119-24