Cryo-EM reveals species-specific components within the Helicobacter pylori Cag type IV secretion system core complex

Abstract

The pathogenesis of <i>Helicobacter pylori</i>-associated gastric cancer is dependent on delivery of CagA into host cells through a type IV secretion system (T4SS). The <i>H. pylori</i> Cag T4SS includes a large membrane-spanning core complex containing five proteins, organized into an outer membrane cap (OMC), a periplasmic ring (PR) and a stalk. Here, we report cryo-EM reconstructions of a core complex lacking Cag3 and an improved map of the wild-type complex. We define the structures of two unique species-specific components (Cag3 and CagM) and show that Cag3 is structurally similar to CagT. Unexpectedly, components of the OMC are organized in a 1:1:2:2:5 molar ratio (CagY:CagX:CagT:CagM:Cag3). CagX and CagY are components of both the OMC and the PR and bridge the symmetry mismatch between these regions. These results reveal that assembly of the <i>H. pylori</i> T4SS core complex is dependent on incorporation of interwoven species-specific components.