Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Vic., Australia.
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Vic., Australia.
FEBS Lett. 2020 Jun;594(12):2016-2026. doi: 10.1002/1873-3468.13807. Epub 2020 May 30.
Programmed death of infected cells is used by multicellular organisms to counter viral infections. Sheeppox virus encodes for SPPV14, a potent inhibitor of Bcl-2-mediated apoptosis. We reveal the structural basis of apoptosis inhibition by determining crystal structures of SPPV14 bound to BH3 motifs of proapoptotic Bax and Hrk. The structures show that SPPV14 engages BH3 peptides using the canonical ligand-binding groove. Unexpectedly, Arg84 from SPPV14 forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that replaces the canonical ionic interaction seen in almost all host Bcl-2:BH3 motif complexes. These results reveal the flexibility of virus-encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways to retain BH3 binding and prosurvival functionality.
细胞程序性死亡被多细胞生物用于对抗病毒感染。绵羊痘病毒编码了 SPPV14，它是一种强效的 Bcl-2 介导的细胞凋亡抑制剂。我们通过确定 SPPV14 与促凋亡 Bax 和 Hrk 的 BH3 基序结合的晶体结构，揭示了凋亡抑制的结构基础。这些结构表明，SPPV14 使用典型的配体结合槽来结合 BH3 肽。出乎意料的是，SPPV14 的 Arg84 与 BH3 基序中的保守 Asp 形成离子相互作用，以取代几乎所有宿主 Bcl-2:BH3 基序复合物中存在的典型离子相互作用。这些结果揭示了病毒编码的 Bcl-2 蛋白的灵活性，能够模拟内源性宿主信号通路的关键相互作用，从而保留 BH3 结合和生存促进功能。
