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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. Sheeppox virus expresses SPPV14, an inhibitor that intervenes in the pro- or anti-apoptotic pathways mediated by the 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)[1], SPPV14 is a potent inhibitor of Hrk, Bax and Bak (pro-apoptotic)[2]. This protein shares high similarity with DPV022 (deerpox), which is structurally the closest to SPPV14.

Structure

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[2]. The A chain of the SPPV14 protein binds to the B chain of the BH3 peptide 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 central helix (Ⲁ-5) surrounded by six other helices, 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 ionic interactions using R84 with Hrk D42 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[2].

Disease

Relevance

Structural highlights

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