HIV-1 capsid undergoes coupled binding and isomerization by the nuclear pore protein NUP358

Bichel, Katsiaryna; Price, Amanda J.; Schaller, Torsten; Towers, Greg J.; Freund, Stefan; James, Leo C.

doi:10.1186/1742-4690-10-81

Cited by 94 publications

(104 citation statements)

References 65 publications

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“…31). It was recently reported that the cyclophilin domain of Nup358 is an isomerase that catalyzes cistrans isomerization of a proline in HIV-1 CA (P90), which facilitates viral core uncoating and nuclear import of PICs (32). We hypothesize that the CA stability mutants directly or indirectly interfere with the CA-Nup358 interaction, or interaction of the CA with another NE associated protein, which reduce association of the PICs with the NE and diminish nuclear import.…”

Section: Discussionmentioning

confidence: 95%

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Burdick

Pathak

2013

Proc. Natl. Acad. Sci. U.S.A.

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Human cytidine deaminases APOBEC3F (A3F) and APOBEC3G (A3G) are host factors that incorporate into virions and restrict virus replication. We labeled HIV-1 particles with yellow fluorescent protein (YFP)-tagged APOBEC3 proteins and examined their association with preintegration complexes (PICs) in infected cells. Labeling of PICs with A3F-YFP, and to a lesser extent A3G-YFP, could be used to visualize PICs in the nuclei, which was dependent on nuclear pore protein Nup153 but not TNPO3. We show that reverse transcription is not required for nuclear import of PICs, indicating that a viral core uncoating event associated with reverse transcription, and the central DNA flap that forms during reverse transcription, are not required for nuclear import. We also quantify association of cytoplasmic PICs with nuclear envelope (NE) and report that capsid mutations that increase or decrease core stability dramatically reduce NE association and nuclear import of PICs. In addition, we find that nuclear PICs remain close to the NE and are not distributed throughout the nuclei. These results provide tools for tracking retroviral PICs in infected cells and reveal insights into HIV-1 replication.retrovirus | microscopy | early events

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Section: Discussionmentioning

confidence: 95%

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Burdick

Pathak

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…It is noteworthy that CPSF6 and NUP153 not only appear to function in the same nuclear import pathway but also share the same CA binding site. This is reminiscent of CypA and NUP358, which similarly compete for binding [16]. Whether this reflects a sequential pathway, with CypA and CPSF6 operating upstream of NUP358 and NUP153, and what the purpose of this might be, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly

et al. 2014

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The HIV-1 capsid is involved in all infectious steps from reverse transcription to integration site selection, and is the target of multiple host cell and pharmacologic ligands. However, structural studies have been limited to capsid monomers (CA), and the mechanistic basis for how these ligands influence infection is not well understood. Here we show that a multi-subunit interface formed exclusively within CA hexamers mediates binding to linear epitopes within cellular cofactors NUP153 and CPSF6, and is competed for by the antiretroviral compounds PF74 and BI-2. Each ligand is anchored via a shared phenylalanine-glycine (FG) motif to a pocket within the N-terminal domain of one monomer, and all but BI-2 also make essential interactions across the N-terminal domain: C-terminal domain (NTD:CTD) interface to a second monomer. Dissociation of hexamer into CA monomers prevents high affinity interaction with CPSF6 and PF74, and abolishes binding to NUP153. The second interface is conformationally dynamic, but binding of NUP153 or CPSF6 peptides is accommodated by only one conformation. NUP153 and CPSF6 have overlapping binding sites, but each makes unique CA interactions that, when mutated selectively, perturb cofactor dependency. These results reveal that multiple ligands share an overlapping interface in HIV-1 capsid that is lost upon viral disassembly.

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“…18 and 19). The cis-trans isomerization is catalyzed by CypA and Nup358Cyp (18,19). The uncatalyzed reaction is slow (exchange rates of <0.1 s −1 ), whereas in the presence of CypA and NUP358Cyp, isomerization rates of 6.6 and 12.1 s −1 were observed, respectively.…”

Section: Significancementioning

confidence: 99%

Dynamic allostery governs cyclophilin A–HIV capsid interplay

Hou

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

150

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Host factor protein Cyclophilin A (CypA) regulates HIV-1 viral infectivity through direct interactions with the viral capsid, by an unknown mechanism. CypA can either promote or inhibit viral infection, depending on host cell type and HIV-1 capsid (CA) protein sequence. We have examined the role of conformational dynamics on the nanosecond to millisecond timescale in HIV-1 CA assemblies in the escape from CypA dependence, by magic-angle spinning (MAS) NMR and molecular dynamics (MD). Through the analysis of backbone 1H-15N and 1H-13C dipolar tensors and peak intensities from 3D MAS NMR spectra of wild-type and the A92E and G94D CypA escape mutants, we demonstrate that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains exhibits unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters are in quantitative agreement with those calculated from MD trajectories. Remarkably, the CypA loop dynamics of wild-type CA HXB2 assembly is significantly attenuated upon CypA binding, and the dynamics profiles of the A92E and G94D CypA escape mutants closely resemble that of wild-type CA assembly in complex with CypA. These results suggest that CypA loop dynamics is a determining factor in HIV-1's escape from CypA dependence.

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HIV-1 capsid undergoes coupled binding and isomerization by the nuclear pore protein NUP358

Cited by 94 publications

References 65 publications

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly

Dynamic allostery governs cyclophilin A–HIV capsid interplay

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