Abstract
Type VI secretion systems facilitate the delivery of antibacterial effector proteins between neighbouring Gram-negative bacteria. A subset of these effectors harbour N-terminal transmembrane domains (TMDs) implicated in effector translocation across the target cell membrane. However, the abundance and distribution of these TMD-containing effectors has remained unknown. Here, we report the discovery of prePAAR, a conserved motif found in over 6,000 putative TMD-containing effectors. Based on their differing sizes and number of TMDs these effectors fall into two distinct classes that are unified by their requirement for a member of the Eag family of T6SS chaperones for export. Co-crystal structures of class I and class II effector TMD-chaperone complexes from Salmonella Typhimurium and Pseudomonas aeruginosa, respectively, reveals that Eag chaperones mimic transmembrane helical packing to stabilize effector TMDs. In addition to participating in the chaperone-TMD interface, we find that prePAAR functions to facilitate proper folding of the downstream PAAR domain, which is required for effector interaction with the T6SS spike. Taken together, our findings define the mechanism of chaperone-assisted secretion of a widespread family of T6SS membrane protein effectors.
Highlights
Bacteria secrete proteins to facilitate interactions with their surrounding environment
Results prePAAR is a motif found in transmembrane domains (TMDs)-containing effectors that interact with effector-associated gene (Eag) chaperones
We previously showed that EagT6 interacts with the N-terminal TMDs of Tse6, an observation that led us to hypothesize a general role for Eag chaperones in ‘solubilizing’ hydrophobic TMDs of effectors in the aqueous environment of the cytoplasm so they can be loaded into the T6SS apparatus (Figure 1B; Quentin et al, 2018)
Summary
Bacteria secrete proteins to facilitate interactions with their surrounding environment. In Gram-negative bacteria, the transport of proteins across cellular membranes often requires the use of specialized secretion apparatuses found within the cell envelope. One such pathway is the type VI secretion system (T6SS), which in many bacterial species functions to deliver antibacterial effector proteins from the cytoplasm directly into an adjacent bacterial cell via a one-step secretion event (Russell et al, 2011). A critical step that precedes type VI secretion is the selective recruitment of effectors to the T6SS apparatus. Recent work has shown that for many effectors this process requires chaperone proteins, which are thought to maintain effectors in a ‘secretion-competent’ state (Unterweger et al, 2017). To-date, no molecular-level evidence exists to support this idea
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