{"doi":"10.1101/2022.01.26.477893","title":"Multivalent interactions essential for lentiviral integrase function","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 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 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 revealed 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 resulted 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":303146,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":806311,"name":"Vidya Chivukula","orcid":"0000-0001-6200-2659","position":1,"is_corresponding":false},{"id":895209,"name":"Dominika T. Gruszka","orcid":"0000-0003-1675-140X","position":2,"is_corresponding":false},{"id":895210,"name":"Zelin Shan","orcid":"0000-0003-4983-3575","position":3,"is_corresponding":false},{"id":253444,"name":"Parmit K. Singh","orcid":"0000-0002-9657-2526","position":4,"is_corresponding":false},{"id":626565,"name":"Valerie E. Pye","orcid":"0000-0001-9616-2992","position":5,"is_corresponding":false},{"id":895211,"name":"Rebecca McLean","orcid":"0000-0002-4688-3019","position":6,"is_corresponding":false},{"id":467192,"name":"Gregory J. Bedwell","orcid":"0000-0003-0456-0032","position":7,"is_corresponding":false},{"id":277724,"name":"Wen Li","orcid":"0000-0003-0197-0933","position":8,"is_corresponding":false},{"id":277727,"name":"Andrea Nans","orcid":"0000-0002-3791-2447","position":9,"is_corresponding":false},{"id":277723,"name":"Nicola Cook","orcid":"0000-0002-2738-7976","position":10,"is_corresponding":false},{"id":895739,"name":"Hind J. Fadel","orcid":null,"position":11,"is_corresponding":false},{"id":404069,"name":"Eric M. Poeschla","orcid":"0000-0003-1598-5415","position":12,"is_corresponding":false},{"id":895212,"name":"David J. Griffiths","orcid":"0000-0001-9160-0770","position":13,"is_corresponding":false},{"id":456213,"name":"Javier Vargas","orcid":"0000-0001-7519-6106","position":14,"is_corresponding":false},{"id":709717,"name":"Ian A. 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