Crystal structure of the Rous sarcoma virus intasome
Open accessAbstract
Integration of the reverse-transcribed viral DNA into the host genome is an essential step in the life cycle of retroviruses. Retrovirus integrase catalyses insertions of both ends of the linear viral DNA into a host chromosome. Integrase from HIV-1 and closely related retroviruses share the three-domain organization, consisting of a catalytic core domain flanked by amino- and carboxy-terminal domains essential for the concerted integration reaction. Although structures of the tetrameric integrase-DNA complexes have been reported for integrase from prototype foamy virus featuring an additional DNA-binding domain and longer interdomain linkers, the architecture of a canonical three-domain integrase bound to DNA remained elusive. Here we report a crystal structure of the three-domain integrase from Rous sarcoma virus in complex with viral and target DNAs. The structure shows an octameric assembly of integrase, in which a pair of integrase dimers engage viral DNA ends for catalysis while another pair of non-catalytic integrase dimers bridge between the two viral DNA molecules and help capture target DNA. The individual domains of the eight integrase molecules play varying roles to hold the complex together, making an extensive network of protein-DNA and protein-protein contacts that show both conserved and distinct features compared with those observed for prototype foamy virus integrase. Our work highlights the diversity of retrovirus intasome assembly and provides insights into the mechanisms of integration by HIV-1 and related retroviruses.
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All retroviral intasomes have 2-fold symmetry and contain a pair of adjacent active sites bound to 3' viral DNA ends.
“Consistent with their function, all intasomes feature 2-fold symmetry and harbour a pair of juxtaposed active sites engaged with 3’ vDNA ends.”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
The RSV structure description (section labeled Abstract; page unavailable) reports an approximately two-fold symmetrical arrangement, with catalytic subunits engaging viral DNA ends. The paper also compares RSV with PFV, but it does not establish that every retroviral intasome has this arrangement; the claim’s “all” is broader than the evidence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAll intasomes incorporate a conserved intasome core assembly, which is the minimal functional unit and is represented by the PFV structure.
“Despite these differences, all intasomes incorporate the conserved intasome core (CIC) assembly, which is the minimal functional unit and is represented by the PFV structure (Figs. 2A, 3).”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
The section comparing RSV and PFV intasomes (page not provided) says the four-integrase PFV intasome corresponds to the core tetramer of the eight-integrase RSV intasome. It does not establish that all intasomes contain this assembly or explicitly identify it as the minimal functional unit. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSubsequent single-particle cryo-EM structures of alpha-, beta-, delta-retroviral and lentiviral intasomes revealed unexpected diversity in the number of integrase molecules needed to construct the active CIC.
“By leveraging the resolution revolution, subsequent single-particle cryo-EM structures of α-, β-, δ-retroviral and lentiviral intasomes revealed unexpected diversity among the number of IN molecules required to construct the active CIC30–33,37,38.”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
The paper’s Abstract reports an octameric RSV intasome and contrasts it with a tetrameric PFV intasome, supporting diversity in integrase-molecule number. But its RSV structure was determined by crystallography, not single-particle cryo-EM; the paper mentions a cryo-EM structure of a beta-retroviral intasome but does not report the claimed subsequent cryo-EM structures across all four groups. (LLM, conf=0.88)
Experimental — accuracy not yet measuredASLV and MMTV intasomes contain eight integrase chains arranged as a tetramer-of-dimers.
“those from ASLV and mouse mammary tumour virus (MMTV, β-retrovirus) harbour eight IN chains (a tetramer-of-dimers)30,31,39.”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
Intasomes from several retroviral species have been assembled from purified components and visualized by X-ray crystallography or cryo-EM.
“The intasomes from several retroviral species were assembled from purified components and visualised by X-ray crystallography or single-particle cryogenic electron microscopy (cryo-EM)25,29–39 (Figs. 2A, 3).”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
Intasomes from different retroviral genera display unexpected architectural diversity.
“The structures revealed unexpected architectural diversity among intasomes from different retroviral genera.”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
Intasomes from several retroviral species and prokaryotic and eukaryotic transpososomes have been visualized as post-catalytic strand transfer complexes, all showing sharp deformations of target DNA.
“Intasomes from several retroviral species as well as prokaryotic and eukaryotic transpososomes have been visualised as post-catalytic strand transfer complexes, all of which display sharp deformations of target DNA29,30,32,33,37,51–54.”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
Primate lentiviral intasomes are unlikely to crystallize because they tend to stack artificially in solution.
“Although the α-retroviral strand transfer intasome complex structure was solved by X-ray crystallography30, it seems highly doubtful, given their propensities to artificially stack upon one another in solution35,36, that primate lentiviral intasomes would ever crystallize.”
From Structure and function of retroviral integrase (2022) · cites this paper as [30]
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Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
Comparative Protein Modelling by Satisfaction of Spatial Restraints
Šali, A., & Blundell, T. L. (1993) · Journal of Molecular Biology · doi:10.1006/jmbi.1993.1626 · Cited by 12,977 · see citing works
Crystal structure of the nucleosome core particle at 2.8 Å resolution
Luger, K., Mäder, A. W., Richmond, R. K., Sargent, D. F., & Richmond, T. J. (1997) · Nature · doi:10.1038/38444 · Cited by 9,466 · see citing works
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334 · see citing works
Deciphering key features in protein structures with the new ENDscript server
Robert, X., & Gouet, P. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku316 · Cited by 7,053 · see citing works
MOLREP : an Automated Program for Molecular Replacement
Vagin, A. A., & Teplyakov, A. (1997) · Journal of Applied Crystallography · doi:10.1107/s0021889897006766 · Cited by 4,791 · see citing works
Linking Crystallographic Model and Data Quality
Karplus, P. A., & Diederichs, K. (2012) · Science · doi:10.1126/science.1218231 · Cited by 1,781 · see citing works
Retroviral intasome assembly and inhibition of DNA strand transfer
Hare, S., Gupta, S. S., Valkov, E., Engelman, A., & Cherepanov, P. (2010) · Nature · doi:10.1038/nature08784 · Cited by 678 · see citing works
Wang, J.-Y., Ling, H., Yang, W., & Craigie, R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.24.7333 · Cited by 332 · see citing works
Craigie, R., & Bushman, F. D. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006890 · Cited by 327 · see citing works
The mechanism of retroviral integration from X-ray structures of its key intermediates
Maertens, G. N., Hare, S., & Cherepanov, P. (2010) · Nature · doi:10.1038/nature09517 · Cited by 296 · see citing works
Schwartzberg, P., Colicelli, J., & Goff, S. P. (1984) · Cell · doi:10.1016/0092-8674(84)90439-2 · Cited by 242 · see citing works
Quashie, P. K., Mésplède, T., Han, Y.-S., Oliveira, M., Singhroy, D. N., Fujiwara, T., Underwood, M., & Wainberg, M. A. (2011) · Journal of Virology · doi:10.1128/jvi.06591-11 · Cited by 238 · see citing works
The participation of DNA in Rofs sarcoma virus production
Temin, H. M. (1964) · Virology · doi:10.1016/0042-6822(64)90232-6 · Cited by 198 · see citing works
Donehower, L. A., & Varmus, H. E. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.20.6461 · Cited by 183 · see citing works
Grandgenett, D. P., Vora, A. C., & Schiff, R. D. (1978) · Virology · doi:10.1016/0042-6822(78)90046-6 · Cited by 175 · see citing works
Self-citationPanganiban, A. T., & Temin, H. M. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.24.7885 · Cited by 164 · see citing works
Wu, X., Li, Y., Crise, B. J., Burgess, S. M., & Munroe, D. J. (2005) · Journal of Virology · doi:10.1128/jvi.79.8.5211-5214.2005 · Cited by 149 · see citing works
Structural basis for retroviral integration into nucleosomes
Maskell, D. P., Renault, L., Serrao, E., Lesbats, P., Matadeen, R., Hare, S., Lindemann, D., Engelman, A. N., Costa, A., & Cherepanov, P. (2015) · Nature · doi:10.1038/nature14495 · Cited by 138 · see citing works
The Mu transpososome structure sheds light on DDE recombinase evolution
Montaño, S. P., Pigli, Y. Z., & Rice, P. A. (2012) · Nature · doi:10.1038/nature11602 · Cited by 137 · see citing works
Gao, K., Butler, S., & Bushman, F. (2001) · EMBO Journal · doi:10.1093/emboj/20.13.3565 · Cited by 133 · see citing works
Lutzke, R. A. P., & Plasterk, R. H. A. (1998) · Journal of Virology · doi:10.1128/jvi.72.6.4841-4848.1998 · Cited by 124 · see citing works
Yang, Z., Mueser, T. C., Bushman, F. D., & Hyde, C. C. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3463 · Cited by 118 · see citing works
Processing of Viral DNA Ends Channels the HIV-1 Integration Reaction to Concerted Integration*[boxs]
Li, M., & Craigie, R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505367200 · Cited by 107 · see citing works
Chen, H., Wei, S.-Q., & Engelman, A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.24.17358 · Cited by 103 · see citing works
Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function
Ballandras-Colas, A., Brown, M., Cook, N. J., Dewdney, T. G., Demeler, B., Cherepanov, P., Lyumkis, D., & Engelman, A. N. (2016) · Nature · doi:10.1038/nature16955 · Cited by 98 · see citing works
Key determinants of target DNA recognition by retroviral intasomes
Serrao, E., Ballandras-Colas, A., Cherepanov, P., Maertens, G. N., & Engelman, A. N. (2015) · Retrovirology · doi:10.1186/s12977-015-0167-3 · Cited by 62 · see citing works
Harper, A. L., Sudol, M., & Katzman, M. (2003) · Journal of Virology · doi:10.1128/jvi.77.6.3838-3845.2003 · Cited by 43 · see citing works
Lubkowski, J. T., Dauter, Z., Yang, F., et al. (1999) · Biochemistry · doi:10.1021/bi991362q · Cited by 42 · see citing works
Yin, Z., Lapkouski, M., Yang, W., & Craigie, R. (2012) · Protein Science · doi:10.1002/pro.2166 · Cited by 36 · see citing works
Self-citationAvian Retrovirus U3 and U5 DNA Inverted Repeats
Vora, A. C., Chiu, R., McCord, M., Goodarzi, G., Stahl, S. J., Mueser, T. C., Hyde, C. C., & Grandgenett, D. P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.38.23938 · Cited by 36 · see citing works
Self-citationBojja, R. S., Andrake, M. D., Weigand, S., Merkel, G., Yarychkivska, O., Henderson, A., Kummerling, M., & Skalka, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.212571 · Cited by 29 · see citing works
Gupta, K., Curtis, J. E., Krueger, S., Hwang, Y., Cherepanov, P., Bushman, F., & Duyne, G. V. (2012) · Structure · doi:10.1016/j.str.2012.08.023 · Cited by 28 · see citing works
Structural and sequencing analysis of local target DNA recognition by MLV integrase
Aiyer, S., Rossi, P., Malani, N., Schneider, W. M., Chandar, A., Bushman, F. D., Montelione, G. T., & Roth, M. J. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv410 · Cited by 25 · see citing works
Molecular and Genetic Determinants of Rous Sarcoma Virus Integrase for Concerted DNA Integration
Chiu, R., & Grandgenett, D. P. (2003) · Journal of Virology · doi:10.1128/jvi.77.11.6482-6492.2003 · Cited by 21 · see citing works
Self-citationVora, A. C., Bera, S., & Grandgenett, D. P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314270200 · Cited by 17 · see citing works
Self-citationShi, K., Pandey, K. K., Bera, S., Vora, A. C., Grandgenett, D. P., & Aihara, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056892 · Cited by 16 · see citing works
Self-citationPeletskaya, E. N., Andrake, M., Gustchina, A., Merkel, G. W., Alexandratos, J. N., Zhou, D., Bojja, R. S., Satoh, T., Potapov, M., Kogon, A. A., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027751 · Cited by 9 · see citing works
Pandey, K. K., Bera, S., Korolev, S., Campbell, M. A., Yin, Z., Aihara, H., & Grandgenett, D. P. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.573311 · Cited by 8 · see citing works
Self-citationAtomic Resolution Structures of the Core Domain of Avian Sarcoma Virus Integrase and Its D64N Mutant
Lubkowski, J. T., Dauter, Z., Yang, F., et al. (1999) · Biochemistry · doi:10.1021/bi995092n · Cited by 7 · see citing works
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- [8]8. Yang ZN, Mueser TC, Bushman FD, Hyde CC. Crystal structure of an active two-domain derivative of Rous sarcoma virus integrase. Journal of molecular biology. 2000; 296:535-548. DOI: 10.1006/ jmbi.1999.3463 [PubMed: 10669607]
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- Authors
- Yin, Z., Shi, K., Banerjee, S., Pandey, K. K., Bera, S., Grandgenett, D. P., & Aihara, H.
- Affiliations
- University of Minnesota (US)
- Cornell University (US)
- Saint Louis University (US)
- Corresponding author
- Aihara, Hideki
- Venue
- Nature
- Published
- 2016-02
- Volume
- 530
- Issue
- 7590
- Pages
- 362-366
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4881392
- OpenAlex
- W2282549557
- Cited by
- 95
- References
- 44
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 14 · 2017: 12 · 2016: 11
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, P41 GM103403, 06CH11357, DE-AC02-)
- National Institutes of Health (DE-AC02–06CH11357, GM103403, GM109770, AI100682)
- Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
- National Institute of General Medical Sciences (GM109770, DE-AC02-06CH11357, GM-103403, R01GM109770, P41GM103403, R35GM118047)
- National Institute of Allergy and Infectious Diseases (AI087098, AI100682, R33AI087098, R21AI100682, R21AI087098)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, P41 GM103403, 06CH11357)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- Rous sarcoma virus, integrase, intasome, retroviral integration, strand transfer, protein-DNA interactions, protein-protein interaction, HIV-1 integrase
- MeSH terms
- DNA, Viral, Models, Molecular, Protein Binding, HIV-1, Spumavirus, Virus Integration, Crystallography, X-Ray, Integrases, Catalytic Domain, Rous sarcoma virus, Protein Multimerization
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