Intrinsic curvature of the HIV-1 CA hexamer underlies capsid topology and interaction with cyclophilin A

Ni, Tao; Gerard, S.; Zhao, Gongpu; Dent, Kyle; Ning, Jiying; Zhou, Jing; Shi, Jiong; Anderson-Daniels, Jordan; Li, Wen; Jang, Sungwoo; Engelman, Alan; Aiken, Christopher; Zhang, Peijun

doi:10.1038/s41594-020-0467-8

Cited by 45 publications

(45 citation statements)

References 55 publications

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“…In line with the observations made in HIV-1 [4], mature RSV CA forms pseudo-symmetric, intrinsically curved hexamers. However, due to the highly pleomorphic shape of our VLPs, the structural plasticity of the RSV hexamer is significantly more pronounced, resulting in a large structural variety of hexamers adopting 2-fold and 3-fold symmetric assemblies, as well as asymmetric structures, which are distorted by local curvature and geometrical context.…”

Section: Discussionsupporting

confidence: 88%

“…The exact mechanism of how mature retroviral CA assemblies are able to form architectures with such a large variety of different curvatures and molecular interactions, is not yet entirely understood. Recent studies analyzing mature HIV-1 CA tubes suggested that the plasticity of the CA hexamer, specifically its deviation from 6-fold symmetry, defines curvature adaptation in mature cores, without significantly altering the CACTD dimer and trimer interfaces [4,5].…”

Section: Discussionmentioning

confidence: 99%

“…As the virus buds from the cell, the viral protease cleaves Gag into several fragments, including the capsid (CA) protein that then assembles into the mature capsid shell (core), rendering the virus particle infectious. Experiments based on X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and helical reconstruction have provided information about the structure of CA in isolation and in highly regular tubular arrays [1][2][3][4][5]. In stark contrast, authentic retrovirus particles are pleiomorphic, lacking size and shape uniformity, rendering these techniques not applicable.…”

Section: Introductionmentioning

confidence: 99%

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Structure of the mature Rous sarcoma virus lattice reveals a role for IP6 in the formation of the capsid hexamer

Obr

Ricana

Nikulin

et al. 2020

Preprint

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Inositol hexakisphosphate (IP6) is an assembly cofactor for HIV-1. We report here that IP6 is also used for assembly of Rous sarcoma virus (RSV), a retrovirus from a different genus. IP6 was ∼100-fold more potent at promoting RSV mature CA assembly than observed for HIV-1 and removal of IP6 in vivo reduced infectivity by 100-fold. By cryo-electron tomography and subtomogram averaging, mature virus-like particles (VLPs) showed an IP6-like density in the CA hexamer, coordinated by rings of six lysines and six arginines. Phosphate and IP6 had opposing effects on CA in vitro assembly, inducing formation of T=1 icosahedrons and tubes, respectively, implying that phosphate promotes pentamer and IP6 hexamer formation. Subtomogram averaging and classification optimized for analysis of pleomorphic retrovirus particles revealed that the heterogeneity of mature RSV CA polyhedrons results from an unexpected, intrinsic CA hexamer flexibility. In contrast, the CA pentamer forms rigid units organizing the local architecture. These different features of hexamers and pentamers determine the structural mechanism to form CA polyhedrons of variable shape in mature RSV particles.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure of the mature Rous sarcoma virus lattice reveals a role for IP6 in the formation of the capsid hexamer

Obr

Ricana

Nikulin

et al. 2020

Preprint

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“…These water-mediated hydrogen bonds were observable at the side chains of conserved residues at the 2-fold interface (Glu175, Ser149, Trp184), and backbone carbonyls at the 2-fold (Gln176) or 3-fold (Ile201, Ala204) interface. This is in contrast to cryoEM and NMR studies which have suggested that hexamers interact via hydrophobic interfaces [6,7,32]. This conflict could be due to the flatness of the crystalline lattice, as the more native shape of the tubular assemblies used in cryoEM and NMR, or due to different buffers used for crystallization and cryoEM/NMR.…”

Section: X-ray Crystallographymentioning

confidence: 67%

“…Recent advances in structural biology, including the advent of high-resolution cryoelectron microscopy (cryoEM) and cryo-electron tomography (cryoET), have enabled the detailed visualization of capsid protein (CA) assemblies. Recently published structures illustrate the composition of both the mature and immature multimeric lattice architecture of the HIV capsid [5][6][7][8]. Those same techniques have yielded data showing CA assemblies complexed with host factors and with small inhibitory molecules [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Wilbourne

Zhang

2021

Viruses

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Understanding of the construction and function of the HIV capsid has advanced considerably in the last decade. This is due in large part to the development of more sophisticated structural techniques, particularly cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). The capsid is known to be a pleomorphic fullerene cone comprised of capsid protein monomers arranged into 200–250 hexamers and 12 pentamers. The latter of these induce high curvature necessary to close the cone at both ends. CryoEM/cryoET, NMR, and X-ray crystallography have collectively described these interactions to atomic or near-atomic resolutions. Further, these techniques have helped to clarify the role the HIV capsid plays in several parts of the viral life cycle, from reverse transcription to nuclear entry and integration into the host chromosome. This includes visualizing the capsid bound to host factors. Multiple proteins have been shown to interact with the capsid. Cyclophilin A, nucleoporins, and CPSF6 promote viral infectivity, while MxB and Trim5α diminish the viral infectivity. Finally, structural insights into the intra- and intermolecular interactions that govern capsid function have enabled development of small molecules, peptides, and truncated proteins to disrupt or stabilize the capsid to inhibit HIV replication. The most promising of these, GS6207, is now in clinical trial.

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Molecular insight into the specific interactions of the SARS‐Coronavirus‐2 nucleocapsid with RNA and host protein

et al. 2023

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The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) nucleocapsid protein is the most abundantly expressed viral protein during infection where it targets both RNA and host proteins. However, identifying how a single viral protein interacts with so many different targets remains a challenge, providing the impetus here for identifying the interaction sites through multiple methods. Through a combination of nuclear magnetic resonance (NMR), electron microscopy, and biochemical methods, we have characterized nucleocapsid interactions with RNA and with three host proteins, which include human cyclophilin‐A, Pin1, and 14–3–3τ. Regarding RNA interactions, the nucleocapsid protein N‐terminal folded domain preferentially interacts with smaller RNA fragments relative to the C‐terminal region, suggesting an initial RNA engagement is largely dictated by this N‐terminal region followed by weaker interactions to the C‐terminal region. The nucleocapsid protein forms 10 nm ribonuclear complexes with larger RNA fragments that include 200 and 354 nucleic acids, revealing its potential diversity in sequestering different viral genomic regions during viral packaging. Regarding host protein interactions, while the nucleocapsid targets all three host proteins through its serine‐arginine‐rich region, unstructured termini of the nucleocapsid protein also engage host cyclophilin‐A and host 14–3–3τ. Considering these host proteins play roles in innate immunity, the SARS‐CoV‐2 nucleocapsid protein may block the host response by competing interactions. Finally, phosphorylation of the nucleocapsid protein quenches an inherent dynamic exchange process within its serine‐arginine‐rich region. Our studies identify many of the diverse interactions that may be important for SARS‐CoV‐2 pathology during infection.

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Intrinsic curvature of the HIV-1 CA hexamer underlies capsid topology and interaction with cyclophilin A

Cited by 45 publications

References 55 publications

Structure of the mature Rous sarcoma virus lattice reveals a role for IP6 in the formation of the capsid hexamer

Structure of the mature Rous sarcoma virus lattice reveals a role for IP6 in the formation of the capsid hexamer

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Molecular insight into the specific interactions of the SARS‐Coronavirus‐2 nucleocapsid with RNA and host protein

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