Control of membrane barrier during bacterial type-III protein secretion

Type-III secretion systems (T3SSs) of the bacterial flagellum and the evolutionarily related injectisome are capable of translocating proteins with a remarkable speed of several thousand amino acids per second. Here, we investigate how T3SSs are able to transport proteins at such a high rate while preventing the leakage of small molecules. Our mutational and evolutionary analyses demonstrate that an ensemble of conserved methionine residues at the cytoplasmic side of the T3SS channel creates a deformable gasket (M-gasket) around fast-moving substrates undergoing export.

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Fig: Organization of the fT3SS pore:a The export gate is composed of FliP/Q/R in a 5:4:1 stoichiometry and is organized in a corkscrew-like helical structure. The R subunit has structural homology that is split between P (RN) and Q (RC) (see c). b The FliR plug (R-plug) and the M-gasket formed of 5 FliP M-loops are located in the core of the pore, sealing it in the closed conformation. c The N-terminal part of FliR exhibits a strong structural homology with FliP, with the exception of a bulky domain (residues 106–122) in place of the FliP M-gasket. The C-terminus of FliR is similar to FliQ on its full length. The structures in (a) and (b) are based on the PDB entry. The isosurface at downscaled resolution (8 Å) was computed to better illustrate the global shape and organization of the subunits.

The unique physicochemical features of the M-gasket are crucial to preserving the membrane barrier, to accommodate local conformational changes during active secretion, and to maintain the stability of the secretion pore in cooperation with a plug domain (R-plug) and a network of salt-bridges. The conservation of the M-gasket, R-plug, and salt-bridge network suggests a universal mechanism by which the membrane integrity is maintained during high-speed protein translocation in all T3SSs.

Hüsing, S., Halte, M., van Look, U. et al. Control of membrane barrier during bacterial type-III protein secretion. Nat Commun 12, 3999 (2021). https://doi.org/10.1038/s41467-021-24226-1

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