La Trobe Institute for Molecular Science, Department of Biochemistry and Genetics, La Trobe University, Melbourne, VIC 3086, Australia.
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, Australia.
Viruses. 2021 Jul 15;13(7):1374. doi: 10.3390/v13071374.
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 , 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.
许多病毒已经进化出了复杂的对策，以劫持宿主细胞对感染的早期程序性细胞死亡，包括使用与 Bcl-2 序列或结构同源的蛋白质。口疮病毒是疱疹病毒科的一员，编码 Bcl-2 同源物 ORFV125，它是宿主中 Bcl-2 介导的细胞凋亡的有效抑制剂。ORFV125 通过直接与宿主促凋亡 Bcl-2 蛋白（包括 Bak 和 Bax）以及 BH3 仅蛋白（如 Hrk 和 Puma）结合而起作用。在这里，我们确定了 ORFV125 与促凋亡蛋白 Puma 和 Hrk 的 BH3 基序结合的晶体结构。这些结构表明，ORFV125 使用典型的配体结合槽与促凋亡 BH3 基序肽结合。位于 ORFV125 结构等效的 BH1 区域的 Arg 与 BH3 基序中的保守 Asp 形成离子相互作用，这种方式模拟了在宿主 Bcl-2:BH3 基序复合物中观察到的典型离子相互作用。这些发现为口疮病毒介导的宿主细胞凋亡抑制提供了结构基础，并揭示了病毒编码的 Bcl-2 蛋白模拟内源性宿主信号通路关键相互作用的灵活性。
