Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia.
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, Australia.
Viruses. 2022 Mar 31;14(4):738. doi: 10.3390/v14040738.
Numerous large DNA viruses have evolved sophisticated countermeasures to hijack the premature programmed cell death of host cells post-infection, including the expression of proteins homologous in sequence, structure, or function to cellular Bcl-2 proteins. Kaposi sarcoma herpes virus (KSHV), a member of the , has been shown to encode for KsBcl-2, a potent inhibitor of Bcl-2 mediated apoptosis. KsBcl-2 acts by directly engaging host pro-apoptotic Bcl-2 proteins including Bak, Bax and Bok, the BH3-only proteins; Bim, Bid, Bik, Hrk, Noxa and Puma. Here we determined the crystal structures of KsBcl-2 bound to the BH3 motif of pro-apoptotic proteins Bid and Puma. The structures reveal that KsBcl-2 engages pro-apoptotic BH3 motif peptides using the canonical ligand binding groove. Thus, the presence of the readily identifiable conserved BH1 motif sequence "NWGR" of KsBcl-2, as well as highly conserved Arg residue (R86) 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 KSHV 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.
许多大型 DNA 病毒已经进化出了复杂的对策，以劫持宿主细胞感染后的过早程序性细胞死亡，包括表达与细胞 Bcl-2 蛋白在序列、结构或功能上同源的蛋白质。卡波西肉瘤疱疹病毒（KSHV）是疱疹病毒科的一员，已被证明能编码 KsBcl-2，它是 Bcl-2 介导的细胞凋亡的有效抑制剂。KsBcl-2 通过直接结合宿主促凋亡的 Bcl-2 蛋白，包括 Bak、Bax 和 Bok（BH3-only 蛋白）；Bim、Bid、Bik、Hrk、Noxa 和 Puma。在这里，我们确定了 KsBcl-2 与促凋亡蛋白 Bid 和 Puma 的 BH3 结构域结合的晶体结构。这些结构表明，KsBcl-2 使用典型的配体结合槽来结合促凋亡的 BH3 结构域肽。因此，KsBcl-2 存在可识别的保守 BH1 模体序列“NWGR”，以及高度保守的 Arg 残基（R86），以类似于宿主 Bcl-2:BH3 结构域复合物中所见的典型离子相互作用的方式与 BH3 结构域中的保守 Asp 形成离子相互作用。这些发现为 KSHV 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 蛋白模仿内源性宿主信号通路关键相互作用的灵活性。
