Multivalent interactions essential for lentiviral integrase function

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 J. Fadel, Eric M. Poeschla, David J. Griffiths, Javier Vargas, Ian A. Taylor, Dmitry Lyumkis (), Hasan Yardimci (), Alan N. Engelman () and Peter Cherepanov ()
Additional contact information
Allison Ballandras-Colas: The Francis Crick Institute
Vidya Chivukula: The Francis Crick Institute
Dominika T. Gruszka: The Francis Crick Institute
Zelin Shan: Laboratory of Genetics, The Salk Institute for Biological Studies
Parmit K. Singh: Dana-Farber Cancer Institute
Valerie E. Pye: The Francis Crick Institute
Rebecca K. McLean: Pentlands Science Park, Bush Loan
Gregory J. Bedwell: Dana-Farber Cancer Institute
Wen Li: Dana-Farber Cancer Institute
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
Hasan Yardimci: The Francis Crick Institute
Alan N. Engelman: Dana-Farber Cancer Institute
Peter Cherepanov: The Francis Crick Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29928-8

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