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Structure of the replicative helicase of the oncoprotein SV40 large tumour antigen

Nature volume 423, pages 512–518 (2003)Cite this article

A Corrigendum to this article was published on 04 September 2003

Abstract

The oncoprotein large tumour antigen (LTag) is encoded by the DNA tumour virus simian virus 40. LTag transforms cells and induces tumours in animals by altering the functions of tumour suppressors (including pRB and p53) and other key cellular proteins. LTag is also a molecular machine that distorts/melts the replication origin of the viral genome and unwinds duplex DNA. LTag therefore seems to be a functional homologue of the eukaryotic minichromosome maintenance (MCM) complex. Here we present the X-ray structure of a hexameric LTag with DNA helicase activity. The structure identifies the p53-binding surface and reveals the structural basis of hexamerization. The hexamer contains a long, positively charged channel with an unusually large central chamber that binds both single-stranded and double-stranded DNA. The hexamer organizes into two tiers that can potentially rotate relative to each other through connecting α-helices to expand/constrict the channel, producing an ‘iris’ effect that could be used for distorting or melting the origin and unwinding DNA at the replication fork.

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Figure 1: The helicase activity and hexamer structure of LTag251–627.
Figure 4: The p53-binding surface.
Figure 2: Detailed structure of LTag251–627 monomer.
Figure 3: Hexamerization of LTag.
Figure 5: The channel features and DNA-binding activity of LTag hexamer.
Figure 6: Models for origin distortion and melting, and DNA unwinding, by LTag.

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Acknowledgements

We thank L.G. Chen for her assistance in the artwork, R. Garcea and L. Chen for comments on the manuscript, other members of the X. Chen laboratory for help and input, staff at 19id and 14bmc in Argonne National Laboratory and at X25 in Brookhaven National Laboratory for assistance in data collection, and the UCHSC X-ray centre in the Biomolecular Structure Program for support. This work is supported in part by start-up and cancer-centre funds from UCHSC to X.C. and NIH-R01 to X.C., J.A.D. and E.F., and a DOE grant to R.Z. and A.J.

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Author notes

  1. Dawei Li

    Present address: National Laboratory, China Agriculture University, Beijing, 100049, China

  2. Dawei Li, Rui Zhao and Ellen Fanning: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Colorado Health Science Center, School of Medicine, Denver, Colorado, 80262, USA

    Dawei Li, Rui Zhao, Wayne Lilyestrom, Dahai Gai, Gerda Szakonyi & Xiaojiang S. Chen

  2. Advanced Photon Source, SBC, Argonne National Laboratory, Argonne, Illinois, 60439, USA

    Rongguang Zhang & Andrzej Jochimiak

  3. Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, 02115, USA

    James A. DeCaprio

  4. Biological Sciences, Vanderbilt University, VU Station B 1634, Nashville, Tennessee, 37235, USA

    Ellen Fanning

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Li, D., Zhao, R., Lilyestrom, W. et al. Structure of the replicative helicase of the oncoprotein SV40 large tumour antigen. Nature 423, 512–518 (2003). https://doi.org/10.1038/nature01691

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