An Invariant Surface Patch on the TRIM5α PRYSPRY Domain Is Required for Retroviral Restriction but Dispensable for Capsid Binding

Sebastian, Sarah; Grütter, Christian; Strambio‐De‐Castillia, Caterina; Pertel, Thomas; Olivari, Silvia; Grütter, Markus G.; Luban, Jeremy

doi:10.1128/jvi.00432-08

Cited by 25 publications

(28 citation statements)

References 55 publications

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“…Accordingly, it is anticipated that the PRYSPRY domain of both SNTX subunits would be responsible for initial interaction with the cell surface through either lipid-or protein-mediated interactions. Consistent with this idea, the canonical protein/lipid binding pocket of each PRYSPRY domain (27) is located at the solvent-exposed base of each SNTX molecule (Fig. 3A).…”

Section: Significancesupporting

confidence: 64%

Stonefish toxin defines an ancient branch of the perforin-like superfamily

Ellisdon

Reboul

Panjikar

et al. 2015

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

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The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack ComplexPerforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (α and β), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX-like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom.H uman envenoming by the tropical stonefish (Synanceia horrida and related species) results in extreme pain, edema, hypotension, respiratory distress, and on rare occasions, death (1). The lethal factor in stonefish venom is an ∼150-kDa protein termed stonustoxin (SNTX), an unusual example of a vertebrate cytolytic protein complex (2). SNTX is a soluble heterodimeric assembly of two closely related proteins termed SNTX-α and -β that share sequence identity of ∼50% (3). With the exception of a C-terminal PRY SPla and the RYanodine Receptor (PRYSPRY) domain in each protein (4), SNTX shares no obvious sequence similarity to any structurally or functionally characterized molecule. SNTX induces species-specific hemolytic activity (2) by an apparent pore-forming mechanism (5). It induces platelet aggregation (6), and like the closely related Trachynilysin (from Synanceia trachynis), SNTX exhibits activity suggesting that it may function as a neurotoxin (7,8).Because eukaryote pore-forming toxins are relatively rare, we reasoned that SNTX might represent a new exemplar of a vertebrate pore-forming protein. Previous studies had shown that it was possible to purify and crystallize SNTX (9); however, no structure has been reported to date. Accordingly, to address the structural basis for SNTX activity, we determined its X-ray crystal structure.

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Section: Significancesupporting

confidence: 64%

Stonefish toxin defines an ancient branch of the perforin-like superfamily

Ellisdon

Reboul

Panjikar

et al. 2015

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

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“…46 In this model, the variable region v1 forms a loop that protrudes from the rest of the domain and is essentially an insertion compared with other SPRY domains. Owing to its flexibility, the exact spatial conformation of this region is more uncertain than that of the more structured globular core.…”

Section: Targeted Mutagenesis Of Arg332 and Arg335 Within Pryspry Firmentioning

confidence: 99%

Generation of human TRIM5α mutants with high HIV-1 restriction activity

et al. 2010

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“…We asked whether the requirements of retroviral restriction for specific TRIM5␣ RING functions depended on capsid binding affinity, which is primarily dictated by the B30.2/SPRY domain (34)(35)(36)(37)(38)(39)(40). To that end, the B30.2/SPRY domain of TRIM5␣ hu was substituted for the B30.2/SPRY domain of wild-type TRIM5␣ rh and three RING domain mutants of TRIM5␣ rh .…”

Section: Antiretroviral Activities Of Trim5␣ Rh Ring Domain Mutantsmentioning

confidence: 99%

“…TRIM5␣, in addition, contains a B30.2/SPRY domain at the C terminus (32,33). The B30.2/SPRY domain determines viral specificity and restriction potency; sequence variations in this domain correlate with the ability of TRIM5 to recognize different viral capsids (34)(35)(36)(37)(38)(39)(40). The coiledcoil domain of TRIM5 is essential for dimerization (41).…”

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confidence: 99%

Virus-Specific Effects of TRIM5α _rh RING Domain Functions on Restriction of Retroviruses

Kim

Song

et al. 2013

J Virol

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T he replication of human immunodeficiency virus type 1 (HIV-1) is potently blocked in Old World monkeys at an early postentry step, prior to reverse transcription (1, 2). In 2004, TRIM5␣ was identified as the major host factor that mediates this block (3). Since this discovery, the TRIM5 proteins of multiple mammalian species have been characterized, and the range of restricted viruses has expanded to include a variety of retroviruses (lentiviruses, a betaretrovirus, a gammaretrovirus, and spumaviruses) (4-16). A TRIM5 variant, TRIMCyp, which arose as a result of retrotransposition events involving TRIM5 and cyclophilin A, exhibits distinct restriction activities and has been identified in New World owl monkeys and some Old World macaque species (17-22). The wide existence of restricting TRIM5 variants suggests that they are part of a novel, widespread mechanism of innate immunity.TRIM5 proteins block viral infection in a species-specific manner. Rhesus monkey TRIM5␣ (TRIM5␣ rh ) potently blocks infection by HIV-1, whereas human TRIM5␣ (TRIM5␣ hu ) only modestly restricts HIV-1 infection but potently blocks infection of N-tropic murine leukemia virus (N-MLV) (3,5,8,9,15). The mechanism of TRIM5-mediated restriction is still not completely understood. Retroviral sensitivity is determined by viral capsid proteins; TRIM5␣ has been shown to bind directly to in vitroassembled HIV-1 capsid-nucleocapsid (CA-NC) complexes, which resemble authentic viral cores (23-25). Interactions between TRIM5 proteins and viral capsids promote the uncoating of sensitive viruses, as the level of particulate capsids is decreased in the cytosol of cells expressing a restricting TRIM5␣ protein (25,26). Recent electron microscopic studies (27) demonstrated that purified TRIM5␣ proteins spontaneously form a large hexagonal lattice structure on the HIV-1 capsid, which is composed of smaller CA hexameric units. This observation has led to the hypothesis that a slight mismatch between the geometry of the TRIM5␣ rh hexagonal lattice and that of the capsid could lead to disassembly of the capsid (27). Some investigators have reported that proteasome inhibitors relieve the TRIM5␣-mediated block of viral reverse transcription but not infection, implying a two-step restriction mechanism that requires the proteasome (28, 29). Degradation of TRIM5 proteins was also observed in the presence of saturating levels of sensitive viruses, suggesting that the TRIM5␣-capsid complexes are targeted for degradation; however, changes in capsid protein stability or accumulation of ubiquitinated TRIM5␣ proteins were not observed upon HIV-1 infection (30). Recognition of the retroviral capsid by TRIM5␣ has been shown to promote innate immune signaling by catalyzing the synthesis of unattached K63 ubiquitin chains (31).TRIM5␣ is a member of the tripartite motif (TRIM) protein family (32). TRIM proteins all contain a RING domain, one or two B-box domains, and a coiled-coil domain. TRIM5␣, in addition, contains a B30.2/SPRY domain at the C terminus (32, 33). The B30.2...

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An Invariant Surface Patch on the TRIM5α PRYSPRY Domain Is Required for Retroviral Restriction but Dispensable for Capsid Binding

Cited by 25 publications

References 55 publications

Stonefish toxin defines an ancient branch of the perforin-like superfamily

Stonefish toxin defines an ancient branch of the perforin-like superfamily

Generation of human TRIM5α mutants with high HIV-1 restriction activity

Virus-Specific Effects of TRIM5α _rh RING Domain Functions on Restriction of Retroviruses

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An Invariant Surface Patch on the TRIM5α PRYSPRY Domain Is Required for Retroviral Restriction but Dispensable for Capsid Binding

Cited by 25 publications

References 55 publications

Stonefish toxin defines an ancient branch of the perforin-like superfamily

Stonefish toxin defines an ancient branch of the perforin-like superfamily

Generation of human TRIM5α mutants with high HIV-1 restriction activity

Virus-Specific Effects of TRIM5α rh RING Domain Functions on Restriction of Retroviruses

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Virus-Specific Effects of TRIM5α _rh RING Domain Functions on Restriction of Retroviruses