Crystal structures of the sheeppox virus encoded inhibitor of apoptosis SPPV14 bound to the proapoptotic BH3 peptides Hrk and Bax

Suraweera, Chathura D.; Burton, Denis R.; Hinds, Mark G.; Kvansakul, Marc

doi:10.1002/1873-3468.13807

Cited by 9 publications

(14 citation statements)

References 59 publications

(53 reference statements)

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“…For example, the SPPV14 protein encoded by the sheeppox virus (SPPV) is a Bcl-2 homolog that can interact with and inhibit the function of a broad spectrum of pro-apoptotic proteins including Bim, Bid, Bmf, Hrk, Puma, Bax and Bak. This way the SPPV14 protein functions as a potent anti-apoptosis viral protein [45,48]. For more similar cases, please see Fig.…”

Section: Accepted Articlementioning

confidence: 95%

“…The BCL-2 protein family is located predominantly on the mitochondria and controls the integrity of the MOM, where they either initiate or prevent the release of apoptogenic factors [43][44][45][46]. This protein family is composed of anti-apoptotic multidomain proteins (e.g., Bcl-2, Bcl-XL, Mcl-1), pro-apoptotic multidomain proteins (e.g., Bax, Bak), and pro-apoptotic BH3-only proteins (e.g., Bid, Bad, Noxa, Bik) [47].…”

Section: Modulation Of Intrinsic Apoptosis and Caspase-9 Activitymentioning

confidence: 99%

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Regulation of innate immune responses by cell death‐associated caspases during virus infection

Fang

Peng

2021

The FEBS Journal

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Viruses are obligate intracellular pathogens that rely on cellular machinery for successful replication and dissemination. The host cells encode a number of different strategies to sense and restrict the invading viral pathogens. Caspase‐mediated programmed cell death pathways that are triggered by virus infection, such as apoptosis and pyroptosis, provide a means for the infected cells to limit viral proliferation, leading to suicidal cell death (apoptosis) or lytic cell death and alerting uninfected cells to mount anti‐viral responses (pyroptosis). However, some viruses can employ activated caspases to dampen the anti‐viral responses and facilitate viral replication through cleavage of critical molecules of the innate immune pathways. The regulation of innate immune responses by caspase activation during virus infection has recently become an important topic. In this review, we briefly introduce the characteristics of different classes of caspases and the cell death pathways regulated by these caspases. We then describe how viruses trigger or dampen caspase activation during infection and how these activated caspases regulate three major innate immune response pathways of viral infections: the retinoic acid‐inducible gene I‐like receptor, toll‐like receptor and cyclic GMP‐AMP synthase‐stimulator of interferon genes pathways.

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Section: Accepted Articlementioning

confidence: 95%

Section: Modulation Of Intrinsic Apoptosis and Caspase-9 Activitymentioning

confidence: 99%

Regulation of innate immune responses by cell death‐associated caspases during virus infection

Fang

Peng

2021

The FEBS Journal

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“…The hallmark interaction between the Arg residue from the NWGR motif and the Asp from the BH3 motif peptide is present in both complexes; the equivalent region of the BH1 motif in ORFV125 is formed by the sequence ‘SPGR’ whereas in TANV16L it is ‘NDNR’, with both contributing to binding and specificity [ 30 ] ( Figure 3 C). A similar observation was made for both sheeppox virus SPPV14 [ 48 ] and deerpox virus DPV022 [ 29 ], which utilize a different Arg to recapitulate the hallmark ionic interaction observed for mammalian pro-survival Bcl-2 proteins bound to BH3 motif bearing interactors [ 4 ]. These observations underscore the major importance of the BH1 equivalent region for determining interactions between Bcl-2 family proteins [ 4 ].…”

Section: Discussionmentioning

confidence: 54%

“…Bcl-2 homologs are widely used amongst large DNA viruses to ensure viral proliferation and/or survival [ 2 , 13 , 43 ]. Amongst the poxviridae, the majority of genera have been shown to encode apoptosis inhibiting Bcl-2 homologs including the orthopoxviridae vaccinia virus F1L [ 27 , 28 ], variola F1L [ 26 ] and ectromelia viruses EMV025 [ 44 ], leporipoxviridae myxomavirus M11L [ 45 ], cervidpoxviridae deerpox virus DPV022 [ 29 , 46 ], capripoxviridae sheeppox virus SPPV14 [ 47 , 48 ], avipoxviridae fowlpoxvirus FPV039 [ 49 ] and canarypox virus CNP058 [ 50 ], yatapoxviridae tanapox virus TANV16L [ 30 ] and parapoxviridae orf virus ORFV125 [ 23 , 24 , 25 ]. Whilst many poxviridae encode for sequence, structural or functional pro-survival Bcl-2 homologs, considerable diversity exists amongst these proteins [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Structural Investigation of Orf Virus Bcl-2 Homolog ORFV125 Interactions with BH3-Motifs from BH3-Only Proteins Puma and Hrk

Suraweera

Hinds

Kvansakul

2021

Viruses

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Numerous viruses have evolved sophisticated countermeasures to hijack the early programmed cell death of host cells in response to infection, including the use of proteins homologous in sequence or structure to Bcl-2. Orf virus, a member of the parapoxviridae, encodes for the Bcl-2 homolog ORFV125, a potent inhibitor of Bcl-2-mediated apoptosis in the host. ORFV125 acts by directly engaging host proapoptotic Bcl-2 proteins including Bak and Bax as well as the BH3-only proteins Hrk and Puma. Here, we determined the crystal structures of ORFV125 bound to the BH3 motif of proapoptotic proteins Puma and Hrk. The structures reveal that ORFV125 engages proapoptotic BH3 motif peptides using the canonical ligand binding groove. An Arg located in the structurally equivalent BH1 region of ORFV125 forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for Orf virus-mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways.

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“…However, the largest number of Bcl-2 homologs is found in poxviridae [12] such as vaccinia and variola virus F1L [23][24][25] and myxomavirus M11L [26][27][28]. Whilst structural studies have shown [18,21,24,[29][30][31][32] these virus-encoded Bcl-2 homologs that adopt a Bcl-2 fold, there is substantial diversity with regard to which proapoptotic host Bcl-2 proteins they bind. For example, vaccinia virus F1L binds Bim, Bak and Bax only [33], whereas sheeppoxvirus SPPV14 binds Bid, Bim, Bmf, Hrk, Puma, Bak and Bax [34], and African swine fever virus A179L binds all major proapoptotic Bcl-2 proteins [18].…”

Section: Introductionmentioning

confidence: 99%

Structural insight into tanapoxvirus‐mediated inhibition of apoptosis

et al. 2020

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Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double‐stranded DNA virus belonging to the poxviridae that causes mild monkeypox‐like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L. We show that TANV16L is able to bind to a range of peptides spanning the BH3 motif of human proapoptotic Bcl‐2 proteins and is able to counter growth arrest of yeast induced by human Bak and Bax. We then determined the crystal structures of TANV16L bound to three identified interactors, Bax, Bim and Puma BH3. TANV16L adopts a globular Bcl‐2 fold comprising 7 α‐helices and utilizes the canonical Bcl‐2 binding groove to engage proapoptotic host cell Bcl‐2 proteins. Unexpectedly, TANV16L is able to adopt both a monomeric and a domain‐swapped dimeric topology where the α1 helix from one protomer is swapped into a neighbouring unit. Despite adopting two different oligomeric forms, the canonical ligand binding groove in TANV16L remains unchanged from monomer to domain‐swapped dimer. Our results provide a structural and mechanistic basis for tanapoxvirus‐mediated inhibition of host cell apoptosis and reveal the capacity of Bcl‐2 proteins to adopt differential oligomeric states whilst maintaining the canonical ligand binding groove in an unchanged state. Database Structural data are available in the Protein Data Bank (PDB) under the accession numbers http://6TPQ, http://6TQQ and http://6TRR.

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Crystal structures of the sheeppox virus encoded inhibitor of apoptosis SPPV14 bound to the proapoptotic BH3 peptides Hrk and Bax

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 9 publications

References 59 publications

Regulation of innate immune responses by cell death‐associated caspases during virus infection

Regulation of innate immune responses by cell death‐associated caspases during virus infection

Structural Investigation of Orf Virus Bcl-2 Homolog ORFV125 Interactions with BH3-Motifs from BH3-Only Proteins Puma and Hrk

Structural insight into tanapoxvirus‐mediated inhibition of apoptosis

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