Wzx flippase-mediated membrane translocation of sugar polymer precursors in bacteria

Bacterial cell surface polysaccharides confer resistance to external stress and promote survival in biotic and abiotic environments. Glycan assembly often occurs at the periplasmic leaflet of the inner membrane (IM) from undecaprenyl pyrophosphate (UndPP)-linked polysaccharide units via the Wzx/Wzy-dependent pathway. Wzx is an integral IM protein found in Gram-negative and Gram-positive bacteria that mediates IM translocation of UndPP-linked sugar repeats from the cytoplasmic to the periplasmic leaflet; interaction of Wzx with other assembly proteins is indirectly supported by genetic evidence. Topological mapping has indicated 12 α-helical transmembrane segments (TMS), with the number of charged TMS residues fluctuating based on the mapping method used. A novel Wzx tertiary structure model has been built, allowing for substrate-binding or energy-coupling roles to be proposed for functionally important charged and aromatic TMS residues. It has also led to a proposed antiport-like mechanism of Wzx function. Exquisite substrate specificity of Wzx proteins was recently revealed in distinguishing between UndPP-linked substrates with identical main-chain sugar repeats, but differing in the chemical composition of a terminal sugar side-branch cap. The objective of this review is to synthesize the most up-to-date knowledge concerning Wzx flippases and to provide perspective for future investigations in this burgeoning field.