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Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces.
- Source :
-
PLoS pathogens [PLoS Pathog] 2011 Mar; Vol. 7 (3), pp. e1002009. Date of Electronic Publication: 2011 Mar 24. - Publication Year :
- 2011
-
Abstract
- TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5α(rh)) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5α(rh) containing coiled-coil and SPRY domains (CC-SPRY(rh)). Concentration-dependent binding of CC-SPRY(rh) to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRY(rh), but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5α(rh) on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction.
- Subjects :
- Animals
Antiviral Restriction Factors
Capsid Proteins metabolism
HIV-1 immunology
HIV-1 metabolism
Host-Pathogen Interactions
Humans
Macaca mulatta
Membrane Transport Proteins metabolism
Protein Binding
Protein Structure, Tertiary
Sequence Homology, Amino Acid
Species Specificity
Tripartite Motif Proteins
Ubiquitin-Protein Ligases
Zinc Fingers
Capsid metabolism
Carrier Proteins metabolism
HIV-1 pathogenicity
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 21455494
- Full Text :
- https://doi.org/10.1371/journal.ppat.1002009