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Diverse HIV viruses are targeted by a conformationally dynamic antiviral

Nature Structural & Molecular Biology volume 19, pages 411–416 (2012)Cite this article

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Abstract

Rhesus macaque TRIMCyp (RhTC) is a potent primate antiviral host protein that inhibits the replication of diverse HIV viruses. Here we show that it has acquired the ability to target multiple viruses by evolving an active site that interconverts between multiple conformations. Mutations that have relieved active site constraints allow RhTC to dynamically sample conformational space, including radically different conformers that target both HIV-1 and HIV-2 viruses. Introduction of a reversible constraint into RhTC allows specificity to be switched between a single conformation specific for HIV-1 and a dynamic ensemble that targets multiple viruses. These results show that conformational diversity can be used to expand the target diversity of innate immune receptors by supplementing their limited genetic variability with variability in protein structure.

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Figure 1: RhTC binding to HIV capsid proteins (CA) using diverse active site conformations.
Figure 2: NMR analysis of CypA and RhTC backbone mobility.
Figure 3: Relaxation dispersion profiles for loop residues in CypA and RhTC.
Figure 4: An engineered redox-sensitive switch controls the dynamic nature of RhTC.
Figure 5: Comparison of CypA and RhTC binding to different viruses.

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References

  1. Stremlau, M. et al. The cytoplasmic body component TRIM5α restricts HIV-1 infection in old world monkeys. Nature 427, 848–853 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Sayah, D.M. et al. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Wilson, S.J. et al. Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc. Natl. Acad. Sci. USA 105, 3557–3562 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Price, A.J. et al. Active site remodeling switches HIV specificity of antiretroviral TRIMCyp. Nat. Struct. Mol. Biol. 16, 1036–1042 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Virgen, C.A. et al. Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species. Proc. Natl. Acad. Sci. USA 105, 3563–3568 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gamble, T.R. et al. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid. Cell 87, 1285–1294 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Vajdos, F.F. et al. Crystal structure of cyclophilin A complexed with a binding site peptide from the HIV-1 capsid protein. Protein Sci. 6, 2297–2307 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yoo, S. et al. Molecular recognition in the HIV-1 capsid/cyclophilin A complex. J. Mol. Biol. 269, 780–795 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Howard, B.R. et al. Structural insights into the catalytic mechanism of cyclophilin A. Nat. Struct. Biol. 10, 475–481 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Ke, H. Similarities and differences between human cyclophilin A and other beta-barrel structures. Structural refinement at 1.63 Å resolution. J. Mol. Biol. 228, 539–550 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Ottiger, M. et al. The NMR solution conformation of unligated human cyclophilin A. J. Mol. Biol. 272, 64–81 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Eisenmesser, E.Z. et al. Intrinsic dynamics of an enzyme underlies catalysis. Nature 438, 117–121 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Peng, J.W. & Wagner, G. Investigation of protein motions via relaxation measurements. Methods Enzymol. 239, 563–596 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Henzler-Wildman, K.A. et al. A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature 450, 913–916 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Gao, F. et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397, 436–441 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Keckesova, Z., Ylinen, L.M. & Towers, G.J. The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities. Proc. Natl. Acad. Sci. USA 101, 10780–10785 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yap, M.W. et al. Trim5α protein restricts both HIV-1 and murine leukemia virus. Proc. Natl. Acad. Sci. USA 101, 10786–10791 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hatziioannou, T. et al. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5α. Proc. Natl. Acad. Sci. USA 101, 10774–10779 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Diehl, W.E. et al. Identification of post-entry restrictions to Mason-Pfizer monkey virus infection in New World monkey cells. J. Virol. 82, 11140–11151 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yap, M.W. et al. Restriction of foamy viruses by primate TRIM5α. J. Virol. 82, 5429–5439 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ganser-Pornillos, B.K. et al. Hexagonal assembly of a restricting TRIM5α protein. Proc. Natl. Acad. Sci. USA 108, 534–539 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Brown, E.W. et al. A lion lentivirus related to feline immunodeficiency virus: epidemiologic and phylogenetic aspects. J. Virol. 68, 5953–5968 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Leslie, A.G. Recent changes to the MOSFLM package for processing film and image plate data. in Joint CCP4 and ESF-EACBM Newsletter on Protein Crystallography Number 26 (Daresbury Laboratory, 1992).

  24. Collaborative Computational Project N. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).

  25. McCoy, A.J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Emsley, P. et al. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Murshudov, G.N., Vagin, A.A. & Dodson, E.J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D Biol. Crystallogr. 53, 240–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Chen, V.B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Bieri, M. & Gooley, P.R. Automated NMR relaxation dispersion data analysis using NESSY. BMC Bioinformatics 12, 421 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the staff at Beamline ID23-1 of the ESRF (Grenoble, France) and Beamline I03 of the Diamond Light Source (Didcot, UK) for expert assistance and D. Neuhaus and P. Evans for helpful discussions. O. Perisic (MRC Laboratory of Molecular Biology) for plasmids. This work was funded by the Medical Research Council (UK) and the European Research Council (281627-IAI).

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Author notes

  1. Matthew E C Caines and Katsiaryna Bichel: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Protein and Nucleic Acid Chemistry, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    Matthew E C Caines, Katsiaryna Bichel, Amanda J Price, William A McEwan, Stefan M V Freund & Leo C James

  2. Division of Infection and Immunity, Medical Research Council Centre for Medical Molecular Virology, University College London, London, UK

    Greg J Towers

  3. Retrovirus Research Laboratory, Medical Research Council-University of Glasgow Centre for Virus Research, University of Glasgow, UK

    Brian J Willett

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  1. Matthew E C Caines
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Contributions

M.E.C.C. and A.J.P. determined crystal structures and carried out ITC experiments; K.B. did NMR dynamics studies; S.M.V.F. did NMR dynamics studies and co-wrote the manuscript; W.A.M. carried out ITC experiments; G.J.T. and B.J.W. supplied materials and assisted with writing; L.C.J. designed experiments and wrote the manuscript.

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Correspondence to Stefan M V Freund or Leo C James.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Supplementary Table 1 and Supplementary Methods (PDF 2178 kb)

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Caines, M., Bichel, K., Price, A. et al. Diverse HIV viruses are targeted by a conformationally dynamic antiviral. Nat Struct Mol Biol 19, 411–416 (2012). https://doi.org/10.1038/nsmb.2253

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