NMR of Biomolecules Unit, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3528, 28 rue du Dr Roux, 75724, Paris, France.
Biochemistry of Macromolecular Interactions Unit, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS ERL6002, 28 rue du Dr Roux, 75724, Paris, France.
Nat Microbiol. 2017 Dec;2(12):1686-1695. doi: 10.1038/s41564-017-0041-2. Epub 2017 Oct 9.
Many Gram-negative bacteria use type 2 secretion systems (T2SSs) to secrete proteins involved in virulence and adaptation. Transport of folded proteins via T2SS nanomachines requires the assembly of inner membrane-anchored fibres called pseudopili. Although efficient pseudopilus assembly is essential for protein secretion, structure-based functional analyses are required to unravel the mechanistic link between these processes. Here, we report an atomic model for a T2SS pseudopilus from Klebsiella oxytoca, obtained by fitting the NMR structure of its calcium-bound subunit PulG into the ~5-Å-resolution cryo-electron microscopy reconstruction of assembled fibres. This structure reveals the comprehensive network of inter-subunit contacts and unexpected features, including a disordered central region of the PulG helical stem, and highly flexible C-terminal residues on the fibre surface. NMR, mutagenesis and functional analyses highlight the key role of calcium in PulG folding and stability. Fibre disassembly in the absence of calcium provides a basis for pseudopilus length control, essential for protein secretion, and supports the Archimedes screw model for the type 2 secretion mechanism.
许多革兰氏阴性菌使用 II 型分泌系统(T2SS)来分泌与毒力和适应有关的蛋白质。通过 T2SS 纳米机器运输折叠蛋白需要组装称为假菌毛的膜内锚定纤维。尽管有效的假菌毛组装对于蛋白质分泌至关重要,但需要基于结构的功能分析来揭示这些过程之间的机械联系。在这里,我们通过将钙结合亚基 PulG 的 NMR 结构拟合到组装纤维的~5-Å 分辨率冷冻电镜重建中,报告了来自产酸克雷伯氏菌的 T2SS 假菌毛的原子模型。该结构揭示了亚基间接触的综合网络以及意想不到的特征,包括 PulG 螺旋茎的无规中央区域和纤维表面上高度灵活的 C 末端残基。NMR、突变和功能分析突出了钙在 PulG 折叠和稳定性中的关键作用。在没有钙的情况下纤维解体为假菌毛长度控制提供了基础,这对于蛋白质分泌至关重要,并支持 II 型分泌机制的阿基米德螺旋模型。