Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function

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dc.contributor.authorBallandras-Colas, Allison
dc.contributor.authorBrown, Monica
dc.contributor.authorCook, Nicola J.
dc.contributor.authorDewdney, Tamaria G.
dc.contributor.authorDemeler, Borries
dc.contributor.authorCherepanov, Peter
dc.contributor.authorLyumkis, Dmitry
dc.contributor.authorEngelman, Alan N.
dc.date.accessioned2021-10-20T19:06:35Z
dc.date.available2021-10-20T19:06:35Z
dc.date.issued2016
dc.descriptionAccepted author manuscripten_US
dc.description.abstractRetroviral integrase catalyses the integration of viral DNA into host target DNA, which is an essential step in the life cycle of all retroviruses1. Previous structural characterization of integrase–viral DNA complexes, or intasomes, from the spumavirus prototype foamy virus revealed a functional integrase tetramer2,3,4,5, and it is generally believed that intasomes derived from other retroviral genera use tetrameric integrase6,7,8,9. However, the intasomes of orthoretroviruses, which include all known pathogenic species, have not been characterized structurally. Here, using single-particle cryo-electron microscopy and X-ray crystallography, we determine an unexpected octameric integrase architecture for the intasome of the betaretrovirus mouse mammary tumour virus. The structure is composed of two core integrase dimers, which interact with the viral DNA ends and structurally mimic the integrase tetramer of prototype foamy virus, and two flanking integrase dimers that engage the core structure via their integrase carboxy-terminal domains. Contrary to the belief that tetrameric integrase components are sufficient to catalyse integration, the flanking integrase dimers were necessary for mouse mammary tumour virus integrase activity. The integrase octamer solves a conundrum for betaretroviruses as well as alpharetroviruses by providing critical carboxy-terminal domains to the intasome core that cannot be provided in cis because of evolutionarily restrictive catalytic core domain–carboxy-terminal domain linker regions. The octameric architecture of the intasome of mouse mammary tumour virus provides new insight into the structural basis of retroviral DNA integration.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationBallandras-Colas, A., Brown, M., Cook, N. J., Dewdney, T. G., Demeler, B., Cherepanov, P., Lyumkis, D., & Engelman, A. N. (2016). Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature, 530, 358-361. https://doi.org/10.1038/nature16955en_US
dc.identifier.urihttps://hdl.handle.net/10133/6067
dc.language.isoen_USen_US
dc.publisherNature Publishingen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionHarvard Medical Schoolen_US
dc.publisher.institutionThe Salk Institute for Biological Studiesen_US
dc.publisher.institutionThe Francis Crick Instituteen_US
dc.publisher.institutionUniversity of Texas Health Science Center at San Antonioen_US
dc.publisher.institutionImperial College Londonen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.urlhttps://doi.org/10.1038/nature16955en_US
dc.subjectCryoelectron microscopyen_US
dc.subjectDNA recombinationen_US
dc.subjectEnzyme mechanismsen_US
dc.subjectRetrovirusen_US
dc.subjectBetaretroviruses
dc.subject.lcshRetroviruses
dc.titleCryo-EM reveals a novel octameric integrase structure for betaretroviral intasome functionen_US
dc.typeArticleen_US
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