HIV-1 capsid shape, orientation, and entropic elasticity regulate translocation into the nuclear pore complex

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(4)

Опубликована: Янв. 19, 2024

Nuclear import and uncoating of the viral capsid are critical steps in HIV-1 life cycle that serve to transport release genomic material into nucleus. Viral core involves translocating at nuclear pore complex (NPC). Notably, central channel NPC appears often accommodate allow passage intact capsid, though mechanistic details process remain be fully understood. Here, we investigate molecular interactions operate concert between regulate translocation through channel. To this end, develop a “bottom-up” coarse-grained (CG) model human from recently released cryo-electron tomography structure then construct composite membrane-embedded CG models. We find successful cytoplasmic side is contingent on compatibility morphology dimension proper orientation approach side. The dynamics driven by maximizing contacts phenylalanine-glycine nucleoporins capsid. For docked capsids, structural analysis reveals correlated striated patterns lattice disorder likely related intrinsic elasticity. Uncondensed inside augments overall Our results suggest “elasticity” can also aid adapt stress structurally during translocation.

Язык: Английский

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Passage of the HIV capsid cracks the nuclear pore

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Passage of the HIV capsid cracks the nuclear pore

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 23, 2024

Summary Upon infection, human immunodeficiency virus (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T-cells and macrophages. As largest known cargo, enters nuclear pore complex (NPC), driven by interactions with numerous FG-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to passage whether capsids are modified during remains unknown, however. Here, we combined super-resolution correlative microscopy cryo electron tomography molecular simulations study entry HIV-1 in primary We found that cytosolically bound cyclophilin A is stripped off entering NPC, hexagonal lattice largely intact inside beyond central channel. Strikingly, NPC scaffold rings frequently crack passage, consistent computer indicating need for widening. The unique cone shape facilitates helps their rings.

Язык: Английский

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MX2 forms nucleoporin-comprising cytoplasmic biomolecular condensates that lure viral capsids

Cell Host & Microbe, Год журнала: 2024, Номер 32(10), С. 1705 - 1724.e14

Опубликована: Окт. 1, 2024

Human myxovirus resistance 2 (MX2) can restrict HIV-1 and herpesviruses at a post-entry step through process requiring an interaction between MX2 the viral capsids. The involvement of other host cell factors, however, remains poorly understood. Here, we mapped proximity interactome MX2, revealing strong enrichment phenylalanine-glycine (FG)-rich proteins related to nuclear pore complex as well that are part cytoplasmic ribonucleoprotein granules. interacted with these form multiprotein biomolecular condensates were essential for its anti-HIV-1 anti-herpes simplex virus 1 (HSV-1) activity. condensate formation required disordered N-terminal region dimerization. Incoming HSV-1 capsids associated dynamic condensates, preventing entry their genomes. Thus, forms likely act decoys, trapping inducing premature genome release interfere targeting HSV-1.

Язык: Английский

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Opening the gate: Complexity and modularity of the nuclear pore scaffold and basket

Current Opinion in Cell Biology, Год журнала: 2025, Номер 92, С. 102461 - 102461

Опубликована: Янв. 17, 2025

Язык: Английский

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Nanomechanical Characterization of Soft Nanomaterial Using Atomic Force Microscopy

Materials Today Bio, Год журнала: 2025, Номер unknown, С. 101506 - 101506

Опубликована: Янв. 1, 2025

Язык: Английский

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Illuminating an invisible state of the HIV-1 capsid protein CTD dimer using ¹⁹ F NMR and weighted ensemble simulations

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(8)

Опубликована: Фев. 18, 2025

The HIV-1 capsid protein (CA) assembles into a conical shell during viral maturation, encasing and protecting the RNA genome. C-terminal domain (CTD) of two-domain dimerizes, this dimer connects individual chains in mature lattice. Previous NMR studies have shown that different arrangements can be formed by isolated assembled lattices; however, dynamics functional relevance these alternate dimers are unknown. To explore conformational landscape CA-CTD dimer, we carried out atomistic molecular simulations using weighted ensemble path sampling strategy, generating an conformations. Focusing on two forms previously observed via solution NMR, refined to highlight metastable states Markov state model. Experimentally, measured interconversion rates between 19 F showed good agreement with derived from simulations. After identifying key interactions distinguish states, was further experimentally verified through disulfide crosslinking. Our results demonstrate advantages pairing gain insights hidden protein.

Язык: Английский

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Correlative In Situ Cryo-ET Reveals Cellular and Viral Remodeling Associated with Selective HIV-1 Core Nuclear Import

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Abstract Lentiviruses like HIV-1 infect non-dividing cells by traversing the nuclear pore, but studying this process has been challenging due to its scarcity and dynamic nature in infected cells. Here, we developed a robust cell-permeabilization system that recapitulates import established an integrated cryo-correlative workflow combining cryo-CLEM, cryo-FIB, cryo-ET for targeted imaging of process. These advancements enabled successful capture 1,899 cores at various stages import. Statistical structural analyses native wild-type mutant revealed depends on both capsid elasticity pore adaptability, as well factors such CPSF6. Brittle fail enter complex (NPC), while CPSF6-binding-deficient stall inside NPC, resulting impaired Intriguingly, pores function selective filters favoring smaller, tube-shaped cores. Our study opens new avenues dissecting biochemistry biology downstream events including core uncoating potentially integration, with unprecedented detail.

Язык: Английский

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Integrating different approaches for the identification of new disruptors of HIV-1 capsid multimerization

Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер unknown, С. 151572 - 151572

Опубликована: Март 1, 2025

Язык: Английский

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The tubular cavity of tobacco mosaic virus shields mechanical stress and regulates disassembly

Acta Biomaterialia, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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