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Multivalent interactions essential for lentiviral integrase function

Author

Listed:
  • Allison Ballandras-Colas

    (The Francis Crick Institute
    University Grenoble)

  • Vidya Chivukula

    (The Francis Crick Institute
    NYU Grossman School of Medicine)

  • Dominika T. Gruszka

    (The Francis Crick Institute
    University of Oxford)

  • Zelin Shan

    (Laboratory of Genetics, The Salk Institute for Biological Studies)

  • Parmit K. Singh

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Valerie E. Pye

    (The Francis Crick Institute)

  • Rebecca K. McLean

    (Pentlands Science Park, Bush Loan
    The Pirbright Institute)

  • Gregory J. Bedwell

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Wen Li

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Andrea Nans

    (The Francis Crick Institute)

  • Nicola J. Cook

    (The Francis Crick Institute)

  • Hind J. Fadel

    (Division of Infectious Diseases, Mayo Clinic)

  • Eric M. Poeschla

    (University of Colorado Anschutz Medical Campus)

  • David J. Griffiths

    (Pentlands Science Park, Bush Loan)

  • Javier Vargas

    (Universidad Complutense de Madrid)

  • Ian A. Taylor

    (The Francis Crick Institute)

  • Dmitry Lyumkis

    (Laboratory of Genetics, The Salk Institute for Biological Studies
    The Scripps Research Institute)

  • Hasan Yardimci

    (The Francis Crick Institute)

  • Alan N. Engelman

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Peter Cherepanov

    (The Francis Crick Institute
    St-Mary’s Campus, Imperial College London)

Abstract

A multimer of retroviral integrase (IN) synapses viral DNA ends within a stable intasome nucleoprotein complex for integration into a host cell genome. Reconstitution of the intasome from the maedi-visna virus (MVV), an ovine lentivirus, revealed a large assembly containing sixteen IN subunits1. Herein, we report cryo-EM structures of the lentiviral intasome prior to engagement of target DNA and following strand transfer, refined at 3.4 and 3.5 Å resolution, respectively. The structures elucidate details of the protein-protein and protein-DNA interfaces involved in lentiviral intasome formation. We show that the homomeric interfaces involved in IN hexadecamer formation and the α-helical configuration of the linker connecting the C-terminal and catalytic core domains are critical for MVV IN strand transfer activity in vitro and for virus infectivity. Single-molecule microscopy in conjunction with photobleaching reveals that the MVV intasome can bind a variable number, up to sixteen molecules, of the lentivirus-specific host factor LEDGF/p75. Concordantly, ablation of endogenous LEDGF/p75 results in gross redistribution of MVV integration sites in human and ovine cells. Our data confirm the importance of the expanded architecture observed in cryo-EM studies of lentiviral intasomes and suggest that this organization underlies multivalent interactions with chromatin for integration targeting to active genes.

Suggested Citation

  • Allison Ballandras-Colas & Vidya Chivukula & Dominika T. Gruszka & Zelin Shan & Parmit K. Singh & Valerie E. Pye & Rebecca K. McLean & Gregory J. Bedwell & Wen Li & Andrea Nans & Nicola J. Cook & Hind, 2022. "Multivalent interactions essential for lentiviral integrase function," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29928-8
    DOI: 10.1038/s41467-022-29928-8
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    References listed on IDEAS

    as
    1. Michał S. Barski & Jordan J. Minnell & Zuzana Hodakova & Valerie E. Pye & Andrea Nans & Peter Cherepanov & Goedele N. Maertens, 2020. "Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Guillermo Abascal-Palacios & Laura Jochem & Carlos Pla-Prats & Fabienne Beuron & Alessandro Vannini, 2021. "Structural basis of Ty3 retrotransposon integration at RNA Polymerase III-transcribed genes," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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