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Multivalent interactions essential for lentiviral integrase function
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DOI：10.1038/s41467-022-29928-8.png)
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Abstract
En 中文
The authors determined high-resolution cryo-EM structures of the lentiviral intasome - the nucleoprotein complex that inserts viral DNA into a host chromosome - and show that the architecture comprising 16 integrase subunits is critical for its function. 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 subunits(1). 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 angstrom 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 alpha-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.
Keywords:
IMMUNODEFICIENCY-VIRUS TYPE-1
PARTICLE CRYO-EM
HIV-1 INTEGRASE
STRUCTURAL BASIS
CRYSTAL-STRUCTURE
RETROVIRAL INTEGRATION
NUCLEOTIDE-SEQUENCE
LEDGF/P75 INTERACTS
SITE SELECTION
REPLICATION
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