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

Title: Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function
Author(s): Ballandras-Colas, A
Browne, M
Cook, NJ
Dewdney, TG
Domeler, B
Cherepanov, P
Lyumkis, D
Engelman, AN
Item Type: Journal Article
Abstract: Retroviral 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.
Publication Date: 17-Feb-2016
Date of Acceptance: 30-Dec-2015
URI: http://hdl.handle.net/10044/1/43889
DOI: https://dx.doi.org/10.1038/nature16955
ISSN: 0028-0836
Publisher: Nature Publishing Group
Start Page: 358
End Page: 361
Journal / Book Title: Nature
Volume: 530
Issue: 7590
Copyright Statement: © 2016 Macmillan Publishers Limited. All rights reserved.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SARCOMA-VIRUS INTEGRASE
VIRAL-DNA ENDS
PHOTO-CROSS-LINKING
DIVISION-OF-LABOR
HIV-1 INTEGRASE
IN-VITRO
MACROMOLECULAR STRUCTURES
RETROVIRAL INTEGRATION
CRYSTAL-STRUCTURE
STRAND TRANSFER
Catalytic Domain
Cryoelectron Microscopy
Crystallography, X-Ray
DNA, Viral
Integrases
Mammary Tumor Virus, Mouse
Models, Molecular
Protein Multimerization
Protein Structure, Quaternary
Spumavirus
Virus Integration
Mammary Tumor Virus, Mouse
Spumavirus
Integrases
DNA, Viral
Cryoelectron Microscopy
Crystallography, X-Ray
Virus Integration
Catalytic Domain
Protein Structure, Quaternary
Models, Molecular
Protein Multimerization
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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