User:Demétrio Speckhort/Sandbox 1
From Proteopedia
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== The SPPV14 == | == The SPPV14 == | ||
| - | The elimination of infected cells through programmed cell death (apoptosis) is the most common response against infectious agents, acting as a primary defense mechanism. In order to prevail in face of such mechanisms, several viruses express inhibitors that prevent apoptosis, combating the host's innate defenses. [https://en.wikipedia.org/wiki/Sheeppox '''Sheeppox virus'''] expresses '''SPPV14''', an inhibitor that intervenes in the pro- or anti-apoptotic pathways mediated by the [https://en.wikipedia.org/wiki/Bcl-2_family Bcl-2 protein family], exhibiting a high inhibitory capacity for apoptosis in virus-infected cells. Unlike most viral strategies, which target the production of Bcl-2 homologs (anti-apoptotic)<ref name=Okamoto> | + | The elimination of infected cells through programmed cell death (apoptosis) is the most common response against infectious agents, acting as a primary defense mechanism. In order to prevail in face of such mechanisms, several viruses express inhibitors that prevent apoptosis, combating the host's innate defenses. [https://en.wikipedia.org/wiki/Sheeppox '''Sheeppox virus'''] expresses '''SPPV14''', an inhibitor that intervenes in the pro- or anti-apoptotic pathways mediated by the [https://en.wikipedia.org/wiki/Bcl-2_family Bcl-2 protein family], exhibiting a high inhibitory capacity for apoptosis in virus-infected cells. Unlike most viral strategies, which target the production of Bcl-2 homologs (anti-apoptotic)<ref name=Okamoto>PMID 22896610</ref>, SPPV14 is a potent inhibitor of [https://en.wikipedia.org/wiki/HRK_(gene) Hrk], [https://en.wikipedia.org/wiki/Apoptosis_regulator_BAX Bax] and [https://en.wikipedia.org/wiki/Bcl-2_homologous_antagonist_killer Bak] (pro-apoptotic)<ref name=Suraweera>DOI 10.1002/1873-3468.13807</ref>. This protein shares high similarity with DPV022 (deerpox), which is structurally the closest to SPPV14. |
== Structure and Function== | == Structure and Function== | ||
| - | In the crystal structures of SPPV14 bound to BH3 peptide motifs, it is observed that SPPV14 is a monomeric structure. The possibility of it being a homodimer in a cellular context cannot be excluded, but the data show that its active form is monomeric. SPPV14 is a prosurvival protein that utilizes the canonical ligand-binding grove to engage BH3 motif peptides of proapoptotic Bcl-2 proteins<ref>DOI 10.1002/1873-3468.13807</ref>. <scene name='10/1050292/Chain_a/3'>The A chain of the SPPV14 protein</scene> binds to <scene name='10/1050292/Chain_b/2'>the B chain of the BH3 peptide</scene> through specific interactions, which are essential for the formation of the heterodimeric complex AB between SPPV14 and the BH3 peptide. | + | In the crystal structures of SPPV14 bound to BH3 peptide motifs, it is observed that SPPV14 is a monomeric structure. The possibility of it being a homodimer in a cellular context cannot be excluded, but the data show that its active form is monomeric. SPPV14 is a prosurvival protein that utilizes the canonical ligand-binding grove to engage BH3 motif peptides of proapoptotic Bcl-2 proteins<ref name=Suraweera>DOI 10.1002/1873-3468.13807</ref>. <scene name='10/1050292/Chain_a/3'>The A chain of the SPPV14 protein</scene> binds to <scene name='10/1050292/Chain_b/2'>the B chain of the BH3 peptide</scene> through specific interactions, which are essential for the formation of the heterodimeric complex AB between SPPV14 and the BH3 peptide. |
| - | SPPV14 has a globular form, consisting of a <scene name='10/1050292/Chain_a_-_alfa-5_helix/2'>central helix (Ⲁ-5)</scene> surrounded by <scene name='10/1050292/Six_other_helices/1'>six other helices</scene>, thus forming the classical structure and fold of Bcl-2. The canonical binding site of SPPV14 is formed by the Ⲁ2-Ⲁ5 helices. The action of the SPPV14 is by sequestering BH3-only proteins including Bim, Bid, Bmf, Hrk, and Puma as well as Bak and Bax; SPPV14 strongly binds with Hrk and Bax, and the interactions are primarily mediated by the 4 hydrophobic canonical sites present in SPPV14, as well as numerous ionic interactions and hydrogen bonds. Unlike other vBcl-2, SPPV14 forms <scene name='10/1050292/Interaction_r84-hrk_d42/1'>ionic interactions using R84 with Hrk D42</scene> or with Bax D68, reminiscent of a highly conserved ionic bond between Arg in the BH1 region, pro-survival motif of mammals, and the Bcl-2 protein that retains the Asp of the functional BH3 motif<ref name=Okamoto> | + | SPPV14 has a globular form, consisting of a <scene name='10/1050292/Chain_a_-_alfa-5_helix/2'>central helix (Ⲁ-5)</scene> surrounded by <scene name='10/1050292/Six_other_helices/1'>six other helices</scene>, thus forming the classical structure and fold of Bcl-2. The canonical binding site of SPPV14 is formed by the Ⲁ2-Ⲁ5 helices. The action of the SPPV14 is by sequestering BH3-only proteins including Bim, Bid, Bmf, Hrk, and Puma as well as Bak and Bax; SPPV14 strongly binds with Hrk and Bax, and the interactions are primarily mediated by the 4 hydrophobic canonical sites present in SPPV14, as well as numerous ionic interactions and hydrogen bonds. Unlike other vBcl-2, SPPV14 forms <scene name='10/1050292/Interaction_r84-hrk_d42/1'>ionic interactions using R84 with Hrk D42</scene> or with Bax D68, reminiscent of a highly conserved ionic bond between Arg in the BH1 region, pro-survival motif of mammals, and the Bcl-2 protein that retains the Asp of the functional BH3 motif<ref name=Okamoto>DPMID 22896610</ref>. |
Revision as of 17:45, 1 June 2024
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References
- ↑ 1.0 1.1 Okamoto T, Campbell S, Mehta N, Thibault J, Colman PM, Barry M, Huang DC, Kvansakul M. Sheeppox virus SPPV14 encodes a Bcl-2-like cell death inhibitor that counters a distinct set of mammalian proapoptotic proteins. J Virol. 2012 Nov;86(21):11501-11. PMID:22896610 doi:10.1128/JVI.01115-12
- ↑ 2.0 2.1 Suraweera CD, Burton DR, Hinds MG, Kvansakul M. Crystal structures of the sheeppox virus encoded inhibitor of apoptosis SPPV14 bound to the proapoptotic BH3 peptides Hrk and Bax. FEBS Lett. 2020 Jun;594(12):2016-2026. PMID:32390192 doi:10.1002/1873-3468.13807
