Solution structure and dynamics of the Rous sarcoma virus capsid protein and comparison with capsid proteins of other retroviruses 1 1Edited by P. E. Wright

Campos-Olivas, Ramón; Newman, J.; Summers, Michael F.

doi:10.1006/jmbi.1999.3475

Cited by 111 publications

(141 citation statements)

References 68 publications

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“…A similar kinking of helix 2 is observed in the x-ray structure of the CA-CTD of the equine infectious anemia virus (13). NMR structures of the CA-CTDs of the Rous sarcoma virus and human T cell leukemia virus type 1 also display notable deviations from the ideal backbone geometry within the helix 2 segment (14,15). In contrast, helix 2 straightens and adopts ideal helical geometry when packed against a neighboring CA-CTD subunit of the domain-swapped dimer.…”

Section: Discussionsupporting

confidence: 54%

“…First, mutations of the crystal dimer interface residues have a pronounced effect on viral assembly but do not completely block it (12). Second, the interface residues are not conserved in different retroviruses, and the capsids of the Rous sarcoma virus, human T cell leukemia virus type 1, and equine infectious anemia virus all seem to be monomeric in solution at concentrations of up to 1 mM (13)(14)(15). Finally, the critical MHR segment is not located at the dimer interface in the HIV-1 CA-CTD crystal, and the reason for its remarkable conservation in retroviruses is not apparent from the existing CA-CTD dimerization model.…”

mentioning

confidence: 99%

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Domain-swapped dimerization of the HIV-1 capsid C-terminal domain

Ivanov

Tsodikov

Kasanov³

et al. 2007

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

106

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Assembly of the HIV and other retroviruses is primarily driven by the oligomerization of the Gag polyprotein, the major viral structural protein capable of forming virus-like particles even in the absence of all other virally encoded components. Several critical determinants of Gag oligomerization are located in the C-terminal domain of the capsid protein (CA-CTD), which encompasses the most conserved segment in the highly variable Gag protein called the major homology region (MHR). The CA-CTD is thought to function as a dimerization module, although the existing model of CA-CTD dimerization does not readily explain why the conserved residues of the MHR are essential for retroviral assembly. Here we describe an x-ray structure of a distinct domain-swapped variant of the HIV-1 CA-CTD dimer stabilized by a single amino acid deletion. In the domain-swapped structure, the MHR-containing segment forms a major part of the dimerization interface, providing a structural mechanism for the enigmatic function of the MHR in HIV assembly. Our observations suggest that swapping of the MHR segments of adjacent Gag molecules may be a critical intermediate in retroviral assembly.Gag ͉ major homology region ͉ viral assembly

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

Domain-swapped dimerization of the HIV-1 capsid C-terminal domain

Ivanov

Tsodikov

Kasanov³

et al. 2007

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

106

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“…Subsequent NMR transverse relaxation T 1 and steady-state heteronuclear nuclear Overhauser effect (NOE) measurements (16) also showed the rigidity of this structural element with values virtually identical to the rest of the well structured protein backbone. In contrast, the ␤-hairpin in HIV-1 CA exhibited a pattern of significant local mobility (on a fast time scale) in the same type of experiments (17). Thus, the same structural element can exhibit distinct dynamics and orientations in two highly related proteins.…”

mentioning

confidence: 91%

Structural and Dynamics Studies of the D54A Mutant of Human T Cell Leukemia Virus-1 Capsid Protein

Bouamr

Cornilescu

Goff

et al. 2005

Journal of Biological Chemistry

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The human T cell leukemia virus and the human immunodeficiency virus share a highly conserved, predominantly helical two-domain mature capsid (CA) protein structure with an N-terminal ␤-hairpin. Despite overall structural similarity, differences exist in the backbone dynamic properties of the CA N-terminal domain. Since studies with other retroviruses suggest that the ␤-hairpin is critical for formation of a CA-CA interface, we investigated the functional role of the human T cell leukemia virus ␤-hairpin by disrupting the salt bridge between Pro 1 and Asp 54 that stabilizes the ␤-hairpin. NMR 15 N relaxation data were used to characterize the backbone dynamics of the D54A mutant in the context of the N-terminal domains, compared with the wildtype counterpart. Moreover, the effect of the mutation on proteolytic processing and release of virus-like particles (VLPs) from human cells in culture was determined. Conformational and dynamic changes resulting from the mutation were detected by NMR spectroscopy. The mutation also altered the conformation of mature CA in cells and VLPs, as reflected by differential antibody recognition of the wild-type and mutated CA proteins. In contrast, the mutation did not detectably affect antibody recognition of the CA protein precursor or release of VLPs assembled by the precursor, consistent with the fact that the hairpin cannot form in the precursor molecule. The particle morphology and size were not detectably affected. The results indicate that the ␤-hairpin contributes to the overall structure of the mature CA protein and suggest that differences in the backbone dynamics of the ␤-hairpin contribute to mature CA structure, possibly introducing flexibility into interface formation during proteolytic maturation.

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“…Highresolution tertiary structures of the MA, CA, and NC proteins from a number of different orthoretroviruses show that the folds of the individual Gag domains are highly conserved, despite limited primary sequence conservation ( Fig. 1c and reviewed in [9,10]). It can therefore be inferred that they share the same basic architecture, despite significant variations in capsid shape that were historically used to define different retroviral genera.…”

Section: Introductionmentioning

confidence: 99%

The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

409

422

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HIV assembly and replication proceed through formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is initiated by proteolytic processing of Gag, which induces conformational changes in the CA domain and results in assembly of the distinctive conical capsid. Retroviral capsids are organized following the principles of fullerene cones, and the hexagonal CA lattice is stabilized by three distinct interfaces. Recently identified inhibitors of viral maturation act by disrupting the final stage of Gag processing, or by inhibiting formation of a critical intermolecular CA-CA interface in the mature capsid. Following release into a new host cell, the capsid disassembles and host cell factors can potently restrict this stage of retroviral replication. Here, we review the structures of immature and mature HIV virions, focusing on recent studies that have defined the global organization of the immature Gag lattice, identified sites likely to undergo conformational changes during maturation, revealed the molecular structure of the mature capsid lattice, demonstrated that capsid architectures are conserved, identified the first capsid assembly inhibitors, and begun to uncover the remarkable biology of the mature capsid.

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Solution structure and dynamics of the Rous sarcoma virus capsid protein and comparison with capsid proteins of other retroviruses 1 1Edited by P. E. Wright

Cited by 111 publications

References 68 publications

Domain-swapped dimerization of the HIV-1 capsid C-terminal domain

Domain-swapped dimerization of the HIV-1 capsid C-terminal domain

Structural and Dynamics Studies of the D54A Mutant of Human T Cell Leukemia Virus-1 Capsid Protein

The structural biology of HIV assembly

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