Identification of the initial nucleocapsid recognition element in the HIV-1 RNA packaging signal

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dc.contributor.authorDing, Pengfei
dc.contributor.authorKharytonchyk, Siarhei
dc.contributor.authorWaller, Alexis
dc.contributor.authorMbaekwe, Ugonna
dc.contributor.authorBasappa, Sapna
dc.contributor.authorKuo, Nansen
dc.contributor.authorFrank, Heather M.
dc.contributor.authorQuasney, Christina
dc.contributor.authorKidane, Aaron
dc.contributor.authorSwanson, Canessa
dc.contributor.authorVan, Verna
dc.contributor.authorSarkar, Mitali
dc.contributor.authorCannistraci, Emily
dc.contributor.authorChaudhary, Ridhi
dc.contributor.authorFlores, Hana
dc.contributor.authorTelesnitsky, Alice
dc.contributor.authorSummers, Michael F.
dc.date.accessioned2020-08-06T16:18:55Z
dc.date.available2020-08-06T16:18:55Z
dc.date.issued2020-07-09
dc.description.abstractSelective packaging of the HIV-1 genome during virus assembly is mediated by interactions between the dimeric 5ʹ-leader of the unspliced viral RNA and the nucleocapsid (NC) domains of a small number of assembling viral Gag polyproteins. Here, we show that the dimeric 5′-leader contains more than two dozen NC binding sites with affinities ranging from 40 nM to 1.4 μM, and that all high-affinity sites (Kd ≲ 400 nM) reside within a ∼150-nt region of the leader sufficient to promote RNA packaging (core encapsidation signal, ΨCES). The four initial binding sites with highest affinity reside near two symmetrically equivalent three-way junction structures. Unlike the other high-affinity sites, which bind NC with exothermic energetics, binding to these sites occurs endothermically due to concomitant unwinding of a weakly base-paired [UUUU]:[GGAG] helical element. Mutations that stabilize base pairing within this element eliminate NC binding to this site and severely impair RNA packaging into virus-like particles. NMR studies reveal that a recently discovered small-molecule inhibitor of HIV-1 RNA packaging that appears to function by stabilizing the structure of the leader binds directly to the [UUUU]:[GGAG] helix. Our findings suggest a sequential NC binding mechanism for Gag-genome assembly and identify a potential RNA Achilles’ heel to which HIV therapeutics may be targeted.en_US
dc.description.sponsorshipWe thank the Howard Hughes Medical Institute (HHMI) staff at University of Maryland, Baltimore County (UMBC) for technical assistance. This research was supported by research grants from the NIH (National Institute of Allergy and Infectious Diseases [NIAID] Grant 8R01 AI150498 to M.F.S. and A.T., and NIAID Grant U54 AI150470 to A.T.). E.C., H.F., U.M., and A.W. were supported by an NIH/National Institute of General Medical Sciences (NIGMS) MARC U*STAR T34 HHS00001 National Research Service Award to UMBC (2T34 GM008663). A.W. was supported by an NIGMS BUILD grant to UMBC (TL4GM118989, UL1GM118988, and RL5GM118987). R.C. and U.M. were supported by an HHMI undergraduate education grant and the Meyerhoff Scholars Program at UMBCen_US
dc.description.urihttps://www.pnas.org/content/117/30/17737en_US
dc.format.extent10 pagesen_US
dc.genrejournal articlesen_US
dc.identifierdoi:10.13016/m2jcon-tyjj
dc.identifier.citationDing, Pengfei; Kharytonchyk, Siarhei; Waller, Alexis; Mbaekwe, Ugonna; Basappa, Sapna; Kuo, Nansen; Frank, Heather M.; Quasney, Christina; Kidane, Aaron; Swanson, Canessa; Van, Verna; Sarkar, Mitali; Cannistraci, Emily; Chaudhary, Ridhi; Flores, Hana; Telesnitsky, Alice; Summers, Michael F.; Identification of the initial nucleocapsid recognition element in the HIV-1 RNA packaging signal; PNAS July 28, 2020 117 (30) 17737-17746; https://www.pnas.org/content/117/30/17737en_US
dc.identifier.urihttps://doi.org/10.1073/pnas.2008519117
dc.identifier.urihttp://hdl.handle.net/11603/19351
dc.language.isoen_USen_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Chemistry & Biochemistry Department Collection
dc.relation.ispartofUMBC Career Center
dc.relation.ispartofUMBC Graduate School
dc.relation.ispartofUMBC Student Collection
dc.rightsThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
dc.rightsAttribution 4.0 International (CC BY 4.0)*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.titleIdentification of the initial nucleocapsid recognition element in the HIV-1 RNA packaging signalen_US
dc.typeTexten_US

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