One of the striking features of human immunodeficiency virus (HIV) is the capsid, a fullerene cone comprised of pleomorphic capsid protein (CA) that shields the viral genome and recruits cofactors. Despite significant advances in understanding the mechanisms of HIV-1 CA assembly and host factor interactions, HIV-2 CA assembly remains poorly understood. By templating the assembly of HIV-2 CA on functionalized liposomes, we report high-resolution structures of the HIV-2 CA lattice, including both CA hexamers and pentamers, alone and with peptides of host phenylalanine-glycine (FG)-motif proteins Nup153 and CPSF6. While the overall fold and mode of FG-peptide binding is conserved with HIV-1, this study reveals distinctive features of the HIV-2 CA lattice, including differing structural character at regions of host factor interactions and divergence in the mechanism of formation of CA hexamers and pentamers. This study extends our understanding of HIV capsids and highlights an approach facilitating the study of lentiviral capsid biology.
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Structural insights into HIV-2 CA lattice formation and FG-pocket binding revealed by single-particle cryo-EM.
Cell Rep
January 2025
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA. Electronic address:
One of the striking features of human immunodeficiency virus (HIV) is the capsid, a fullerene cone comprised of pleomorphic capsid protein (CA) that shields the viral genome and recruits cofactors. Despite significant advances in understanding the mechanisms of HIV-1 CA assembly and host factor interactions, HIV-2 CA assembly remains poorly understood. By templating the assembly of HIV-2 CA on functionalized liposomes, we report high-resolution structures of the HIV-2 CA lattice, including both CA hexamers and pentamers, alone and with peptides of host phenylalanine-glycine (FG)-motif proteins Nup153 and CPSF6.
View Article and Find Full Text PDFStructural insights into HIV-2 CA lattice formation and FG-pocket binding revealed by single particle cryo-EM.
bioRxiv
October 2024
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
One of the most striking features of HIV is the capsid; a fullerene cone comprised of the pleomorphic capsid protein (CA) which shields the viral genome from cellular defense mechanisms and recruits cellular cofactors to the virus. Despite significant advances in understanding the mechanisms of HIV-1 CA assembly and host factor interaction, HIV-2 CA remains poorly understood. By templating the assembly of HIV-2 CA on functionalized liposomes, we were able to determine high resolution structures of the HIV-2 CA lattice, including both CA hexamers and pentamers, alone and in complexes with peptides of host phenylalanine-glycine (FG)-motif proteins Nup153 and CPSF6.
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J Mol Biol
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Institute for Molecular Virology, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA; Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA; Characterization Facility, College of Sciences and Engineering, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA. Electronic address:
Retrovirus immature particle morphology consists of a membrane enclosed, pleomorphic, spherical and incomplete lattice of Gag hexamers. Previously, we demonstrated that human immunodeficiency virus type 2 (HIV-2) immature particles possess a distinct and extensive Gag lattice morphology. To better understand the nature of the continuously curved hexagonal Gag lattice, we have used the single particle cryo-electron microscopy method to determine the HIV-2 Gag lattice structure for immature virions.
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Institute for Molecular Virology, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA; Division of Basic Sciences, School of Dentistry, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA; Comparative Molecular Biosciences Graduate Program, University of Minnesota - Twin Cities, St. Paul, MN 55108, USA; Biochemistry, Molecular Biology & Biophysics Graduate Program, University of Minnesota - Twin Cities, Minneapolis, MN 55455, USA. Electronic address:
Human immunodeficiency virus (HIV) Gag drives virus particle assembly. The capsid (CA) domain is critical for Gag multimerization mediated by protein-protein interactions. The Gag protein interaction network defines critical aspects of the retroviral lifecycle at steps such as particle assembly and maturation.
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Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
The binding surface on CD4 for the HIV-1 gp120 envelope glycoprotein has been transplanted previously onto a scorpion-toxin scaffold. Here, we use X-ray crystallography to characterize atomic-level details of gp120 with this transplant, CD4M33. Despite known envelope flexibility, the conformation of gp120 induced by CD4M33 was so similar to that induced by CD4 that localized measures were required to distinguish ligand-induced differences from lattice variation.
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