Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid Protein

Ohkura, Sadayuki; Goldstone, David C.; Yap, Melvyn W.; Holden-Dye, Kate; Taylor, Ian A.; Stoye, Jonathan P.

doi:10.1371/journal.ppat.1002011

Cited by 49 publications

(64 citation statements)

References 53 publications

(86 reference statements)

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“…In contrast, V1-V3 of PRY/SPRY rh do not fall into either group, and V1 is significantly longer. These findings reinforce the notion that the variable regions of TRIM5α PRY/SPRY are mostly flexible and have evolved for antiviral activity (29)(30)(31).…”

Section: Resultssupporting

confidence: 85%

“…S4), including the β1/β2 hairpin, L5/6, and L4/5 regions in HIV CA and the corresponding sites on MLV CA (30,33,(45)(46)(47)(48)(49)(50). Specifically, TRIM5α V1 may interact with CA β1/β2 at the center of the CA hexamer, as swapping the V1 region of rhTRIM5α and huTRIM5α resulted in a change of the restriction specificity toward MLV CA with mutations in the β1/β2 region (30). Third, our cryo-EM and cosedimentation experiments reveal that the PRY/SPRY rh domain retains the ability to bind HIV-1 CA helical tubes without breaking the assembly.…”

Section: Discussionmentioning

confidence: 99%

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Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Yang

Zhao

et al. 2012

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

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Tripartite motif protein isoform 5 alpha (TRIM5α) is a potent antiviral protein that restricts infection by HIV-1 and other retroviruses. TRIM5α recognizes the lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a species-specific manner. Upon binding, TRIM5α induces premature disassembly of the viral capsid and activates the downstream innate immune response. We have determined the crystal structure of the rhesus TRIM5α PRY/ SPRY domain that reveals essential features for capsid binding. Combined cryo-electron microscopy and biochemical data show that the monomeric rhesus TRIM5α PRY/SPRY, but not the human TRIM5α PRY/SPRY, can bind to HIV-1 capsid protein assemblies without causing disruption of the capsid. This suggests that the PRY/SPRY domain alone constitutes an important pattern-sensing component of TRIM5α that is capable of interacting with viral capsids of different curvatures. Our results provide molecular insights into the mechanisms of TRIM5α-mediated retroviral restriction.

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Yang

Zhao

et al. 2012

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

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“…3B is larger than the solvent-exposed surface of the capsid N-terminal domain monomer and is likely to recognize epitopes spanning more than one capsid monomer within the hexamer. Such an extended interaction surface with multiple epitopes is consistent with numerous functional studies (28,35,37) and with the analysis of the MLV mutants that escape restriction by TRIM5α (38), which showed that point mutations that compromise restriction are located almost 30 Å apart on the capsid surface.…”

Section: Discussionsupporting

confidence: 86%

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

Biris¹,

Yang

Taylor³

et al. 2012

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

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Tripartite motif protein TRIM5α blocks retroviral replication after cell entry, and species-specific differences in its activity are determined by sequence variations within the C-terminal B30.2/ PRYSPRY domain. Here we report a high-resolution structure of a TRIM5α PRYSPRY domain, the PRYSPRY of the rhesus monkey TRI-M5α that potently restricts HIV infection, and identify features involved in its interaction with the HIV capsid. The extensive capsidbinding interface maps on the structurally divergent face of the protein formed by hypervariable loop segments, confirming that TRIM5α evolution is largely determined by its binding specificity. Interactions with the capsid are mediated by flexible variable loops via a mechanism that parallels antigen recognition by IgM antibodies, a similarity that may help explain some of the unusual functional properties of TRIM5α. Distinctive features of this pathogenrecognition interface, such as structural plasticity conferred by the mobile v1 segment and interaction with multiple epitopes, may allow restriction of divergent retroviruses and increase resistance to capsid mutations.

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“…HIV is not the only retrovirus that successfully counteracts the effects of restriction factors. Some murine leukemia viruses (MLVs) have also developed ways to avoid detection and restriction by host retroviral restriction factors (15)(16)(17)(18).…”

mentioning

confidence: 99%

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

Gerpe

Renner

Bélanger

et al. 2015

J Virol

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Retroviruses are pathogens with rapid infection cycles that can be a source of disease, genome instability, and tumor development in their hosts. Host intrinsic restriction factors, such as APOBEC3 (A3) proteins, are constitutively expressed and dedicated to interfering with the replication cycle of retroviruses. To survive, propagate, and persist, retroviruses must counteract these restriction factors, often by way of virus genome-encoded accessory proteins. Glycosylated Gag, also called glycosylated Pr80 Gag (gPr80), is a gammaretrovirus genome-encoded protein that inhibits the antiretroviral activity of mouse A3 (mA3). Here we show that gPr80 exerts two distinct inhibitory effects on mA3: one that antagonizes deamination-independent restriction and another one that inhibits its deaminase activity. More specifically, we find that the number of N-glycosylated residues in gPr80 inversely correlates with the sensitivity of a gammaretrovirus to deamination by mouse A3 and also, surprisingly, by human A3G. Finally, our work highlights that retroviruses which have successfully integrated into the mouse germ line generally express a gPr80 with fewer glycosylated sites than exogenous retroviruses. This observation supports the suggestion that modulation of A3 deamination intensity could be a desirable attribute for retroviruses to increase genetic diversification and avoid immune detection. Overall, we present here the first description of how gammaretroviruses employ posttranslational modification to antagonize and modulate the activity of a host genome-encoded retroviral restriction factor. IMPORTANCEAPOBEC3 proteins are host factors that have a major role in protecting humans and other mammals against retroviruses. These enzymes hinder their replication and intensely mutate their DNA, thereby inactivating viral progeny and the spread of infection. Here we describe a newly recognized way in which some retroviruses protect themselves against the mutator activity of APOBEC3 proteins. We show that gammaretroviruses expressing an accessory protein called glycosylated Gag, or gPr80, use the host's posttranslational machinery and, more specifically, N-linked glycosylation as a way to modulate their sensitivity to mutations by APOBEC3 proteins. By carefully controlling the amount of mutations caused by APOBEC3 proteins, gammaretroviruses can find a balance that helps them evolve and persist.

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Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid Protein

Cited by 49 publications

References 53 publications

Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Structural insight into HIV-1 capsid recognition by rhesus TRIM5α

Structure of the rhesus monkey TRIM5α PRYSPRY domain, the HIV capsid recognition module

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

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