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  Structures of immature EIAV Gag lattices reveal a conserved role for IP6 in lentivirus assembly

Dick, R. A., Xu, C. Y., Morado, D. R., Kravchuk, V., Ricana, C. L., Lyddon, T. D., et al. (2020). Structures of immature EIAV Gag lattices reveal a conserved role for IP6 in lentivirus assembly. Plos Pathogens, 16(1): e1008277. doi:10.1371/journal.ppat.1008277.

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 Creators:
Dick, R. A., Author
Xu, C. Y., Author
Morado, D. R., Author
Kravchuk, V., Author
Ricana, C. L., Author
Lyddon, T. D., Author
Broad, A. M., Author
Feathers, J. R., Author
Johnson, M. C., Author
Vogt, V. M., Author
Perilla, J. R., Author
Briggs, John A. G.1, 2, Author           
Schur, F. K. M., Author
Affiliations:
1MRC Laboratory of Molecular Biology, External Organizations, ou_3346673              
2European Molecular Biology Laboratory, External Organizations, Heidelberg, DE, ou_3346677              

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Free keywords: molecular-dynamics cryoelectron tomography spacer peptide in-vitro virus protein resolution visualization maturation binding Microbiology Parasitology Virology
 Abstract: Retrovirus assembly is driven by the multidomain structural protein Gag. Interactions between the capsid domains (CA) of Gag result in Gag multimerization, leading to an immature virus particle that is formed by a protein lattice based on dimeric, trimeric, and hexameric protein contacts. Among retroviruses the inter- and intra-hexamer contacts differ, especially in the N-terminal sub-domain of CA (CA(NTD)). For HIV-1 the cellular molecule inositol hexakisphosphate (IP6) interacts with and stabilizes the immature hexamer, and is required for production of infectious virus particles. We have used in vitro assembly, cryo-electron tomography and subtomogram averaging, atomistic molecular dynamics simulations and mutational analyses to study the HIV-related lentivirus equine infectious anemia virus (EIAV). In particular, we sought to understand the structural conservation of the immature lentivirus lattice and the role of IP6 in EIAV assembly. Similar to HIV-1, IP6 strongly promoted in vitro assembly of EIAV Gag proteins into virus-like particles (VLPs), which took three morphologically highly distinct forms: narrow tubes, wide tubes, and spheres. Structural characterization of these VLPs to sub-4 angstrom resolution unexpectedly showed that all three morphologies are based on an immature lattice with preserved key structural components, highlighting the structural versatility of CA to form immature assemblies. A direct comparison between EIAV and HIV revealed that both lentiviruses maintain similar immature interfaces, which are established by both conserved and non-conserved residues. In both EIAV and HIV-1, IP6 regulates immature assembly via conserved lysine residues within the CA(CTD) and SP. Lastly, we demonstrate that IP6 stimulates in vitro assembly of immature particles of several other retroviruses in the lentivirus genus, suggesting a conserved role for IP6 in lentiviral assembly. Author summary The structural polyprotein Gag is conserved among all retroviruses and mediates virus assembly via oligomerization into incomplete lattices that are stabilized by dimeric, trimeric and hexameric contacts. Despite a high degree of conservation at the secondary and tertiary structure level, the quaternary interactions between the CA domains of retroviral Gag vary. Recently, the small cellular molecule IP6 was identified as an assembly co-factor of the lentivirus HIV-1. To better understand the structural variability of retroviruses and to determine if IP6 is an assembly cofactor of other lentiviruses we determined the structure of the HIV-1 related retrovirus EIAV. Using cryo-electron tomography and subtomogram averaging, in vitro assembly, mutation analysis, and molecular dynamic simulations, we determined and characterized the structure of the EIAV immature lattice. Furthermore, we found that IP6 is an assembly cofactor of EIAV, and other lentiviruses.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: Other: WOS:000510746400010
DOI: 10.1371/journal.ppat.1008277
ISSN: 1553-7366
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Title: Plos Pathogens
  Alternative Title : PLoS Pathog.
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 16 (1) Sequence Number: e1008277 Start / End Page: - Identifier: -