Structures of immature EIAV Gag lattices reveal a conserved role for IP6 in lentivirus assembly.
Amino Acid Sequence
Animals
Electron Microscope Tomography
Equine Infectious Anemia
/ metabolism
Gene Products, gag
/ chemistry
HIV Infections
/ metabolism
HIV-1
/ genetics
Horses
Host-Pathogen Interactions
Infectious Anemia Virus, Equine
/ chemistry
Phytic Acid
/ metabolism
Sequence Alignment
Virion
/ genetics
Virus Assembly
gag Gene Products, Human Immunodeficiency Virus
/ chemistry
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
15
07
2019
accepted:
11
12
2019
revised:
06
02
2020
pubmed:
28
1
2020
medline:
6
5
2020
entrez:
28
1
2020
Statut:
epublish
Résumé
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 (CANTD). 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-4Å 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 CACTD 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.
Identifiants
pubmed: 31986188
doi: 10.1371/journal.ppat.1008277
pii: PPATHOGENS-D-19-01294
pmc: PMC7004409
doi:
Substances chimiques
Gene Products, gag
0
gag Gene Products, Human Immunodeficiency Virus
0
Phytic Acid
7IGF0S7R8I
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008277Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM107013
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM082251
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI147890
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM110758
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150454
Pays : United States
Organisme : Medical Research Council
ID : MC_UP_1201/16
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : P50 AI150481
Pays : United States
Organisme : Austrian Science Fund FWF
ID : P 31445
Pays : Austria
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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