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Cited by 122HIV Research and TreatmentHIV/AIDS drug development and treatmentVirus-based gene therapy research

Structural Basis for Functional Tetramerization of Lentiviral Integrase

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Hare, Stephen, Di Nunzio, Francesca, Labeja, Alfred, Wang, Jimin, Engelman, Alan, Cherepanov, Peter·2009·PLoS Pathogens
DOI 10.1371/journal.ppat.1000515PMC PMC2705190
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Abstract

Experimental evidence suggests that a tetramer of integrase (IN) is the protagonist of the concerted strand transfer reaction, whereby both ends of retroviral DNA are inserted into a host cell chromosome. Herein we present two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF. The structures reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N-terminal domains between the inner pair of monomers poised to execute catalytic function. Comparison of four independent IN tetramers in our crystal structures elucidate the basis for the closure of the highly flexible dimer-dimer interface, allowing us to model how a pair of active sites become situated for concerted integration. Using a range of complementary approaches, we demonstrate that the dimer-dimer interface is essential for HIV-1 IN tetramerization, concerted integration in vitro, and virus infectivity. Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor.

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  • The expansion of intasome architecture in alpha-, beta-retroviruses and lentiviruses is dictated by three factors: CCD-CTD linker length, the multimeric state of integrase before assembly, and C-terminal domain properties.

    “The expansion of the intasome architecture in these viruses is dictated by three factors.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [42]

    The Introduction discusses integrase domains and multimerization, while the Discussion describes CCD–CTD linker flexibility and says CTD positions in the tetramer cannot be inferred from the available partial structures. Neither section identifies the three proposed determinants of intasome architecture or compares architectural expansion across alpha-, beta-retroviruses and lentiviruses. Searched for the three factors, linker length, pre-assembly multimeric state, and intasome expansion. (LLM, conf=0.72)

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References 75 · Cited by 122

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Authors
Hare, S., Di Nunzio, F., Labeja, A., Wang, J., Engelman, A., & Cherepanov, P.
Affiliations
  • Imperial College London (GB)
  • Yale University (US)
  • Dana-Farber Cancer Institute (US)
Corresponding author
  • Engelman, Alan
  • Cherepanov, Peter
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2009-07-17
Volume
5
Issue
7
Pages
e1000515
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1000515
PMC
PMC2705190
OpenAlex
W1997754834
Cited by
122
References
75
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 4 · 2020: 9 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 7 · 2015: 4 · 2014: 13 · 2013: 7 · 2012: 9
FWCI
5.02
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Diamond Light Source
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Allergy and Infectious Diseases (R01AI070042, AI070042)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
LEDGF, HIV-1 integrase, maedi-visna virus, dimer interface, retroviral integration, viral infectivity, crystal structure
MeSH terms
Models, Molecular, Mutation, Viral Proteins, Visna-maedi virus, HIV-1, Crystallography, X-Ray, Integrases, HIV Integrase, Intercellular Signaling Peptides and Proteins, vpr Gene Products, Human Immunodeficiency Virus, Protein Interaction Domains and Motifs, Protein Multimerization

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