Department of Biochemistry and Biophysics, Center for Phage Technology, Texas A&M University, College Station, TX 77843.
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):11697-11702. doi: 10.1073/pnas.1707102114. Epub 2017 Oct 16.
In single-stranded RNA bacteriophages (ssRNA phages) a single copy of the maturation protein binds the genomic RNA (gRNA) and is required for attachment of the phage to the host pilus. For the canonical Qβ the maturation protein, A, has an additional role as the lysis protein, by its ability to bind and inhibit MurA, which is involved in peptidoglycan biosynthesis. Here, we determined structures of Qβ virions, virus-like particles, and the Qβ-MurA complex using single-particle cryoelectron microscopy, at 4.7-Å, 3.3-Å, and 6.1-Å resolutions, respectively. We identified the outer surface of the β-region in A as the MurA-binding interface. Moreover, the pattern of MurA mutations that block Qβ lysis and the conformational changes of MurA that facilitate A binding were found to be due to the intimate fit between A and the region encompassing the closed catalytic cleft of substrate-liganded MurA. Additionally, by comparing the Qβ virion with Qβ virus-like particles that lack a maturation protein, we observed a structural rearrangement in the capsid coat proteins that is required to package the viral gRNA in its dominant conformation. Unexpectedly, we found a coat protein dimer sequestered in the interior of the virion. This coat protein dimer binds to the gRNA and interacts with the buried α-region of A, suggesting that it is sequestered during the early stage of capsid formation to promote the gRNA condensation required for genome packaging. These internalized coat proteins are the most asymmetrically arranged major capsid proteins yet observed in virus structures.
在单链 RNA 噬菌体 (ssRNA 噬菌体) 中,成熟蛋白的单个拷贝与基因组 RNA (gRNA) 结合,并且是噬菌体附着在宿主菌毛上所必需的。对于典型的 Qβ,成熟蛋白 A 还有作为裂解蛋白的额外作用,这是通过其结合和抑制参与肽聚糖生物合成的 MurA 的能力来实现的。在这里,我们使用单颗粒冷冻电子显微镜分别在 4.7-Å、3.3-Å 和 6.1-Å 的分辨率下确定了 Qβ 病毒粒子、病毒样颗粒和 Qβ-MurA 复合物的结构。我们确定了 A 中β区域的外表面是 MurA 结合界面。此外,阻止 Qβ裂解的 MurA 突变模式和促进 A 结合的 MurA 构象变化被发现是由于 A 与包含底物结合的 MurA 封闭催化裂缝的区域之间的紧密配合。此外,通过比较缺乏成熟蛋白的 Qβ 病毒粒子和 Qβ 病毒样颗粒,我们观察到衣壳蛋白的结构重排,这是将病毒 gRNA 包装在其优势构象中所必需的。出乎意料的是,我们发现衣壳蛋白二聚体被隔离在病毒粒子的内部。这种衣壳蛋白二聚体与 gRNA 结合,并与埋藏的 A 的α区域相互作用,表明它在衣壳形成的早期被隔离,以促进基因组包装所需的 gRNA 凝聚。这些内化的衣壳蛋白是迄今为止在病毒结构中观察到的最不对称排列的主要衣壳蛋白。