Abstract
Recent years have seen major advances in the structural understanding of the different components of tripartite efflux assemblies, which encompass the multidrug efflux (MDR) pumps and type I secretion systems. The majority of these investigations have focused on the role played by the inner membrane transporters and the outer membrane factor (OMF), leaving the third component of the system – the Periplasmic Adaptor Proteins (PAPs) – relatively understudied. Here we review the current state of knowledge of these versatile proteins which, far from being passive linkers between the OMF and the transporter, emerge as active architects of tripartite assemblies, and play diverse roles in the transport process. Recognition between the PAPs and OMFs is essential for pump assembly and function, and targeting this interaction may provide a novel avenue for combating multidrug resistance. With the recent advances elucidating the drug efflux and energetics of the tripartite assemblies, the understanding of the interaction between the OMFs and PAPs is the last piece remaining in the complete structure of the tripartite pump assembly puzzle.
Highlights
Recent years have seen major advances in the structural understanding of the different components of tripartite efflux assemblies, which encompass the multidrug efflux (MDR) pumps and type I secretion systems. The majority of these investigations have focused on the role played by the inner membrane transporters and the outer membrane factor (OMF), leaving the third component of the system – the Periplasmic Adaptor Proteins (PAPs) – relatively understudied
Tripartite assemblies are a heterogeneous group of multidrug efflux and type I secretion systems which draws from several different families of primary and secondary inner-membrane transporters (MFS, ABC and RND)
With the help of the so-called periplasmic adaptor proteins (PAPs), the inner-membrane transporters are linked to the outer membrane factors (OMFs) of the TolC family to create continuous conduits from the cytoplasm to the extracellular space, shown in Figure 1 (Misra and Bavro, 2009; Hinchliffe et al, 2013; Blair et al, 2014, 2015; Zgurskaya et al, 2015)
Summary
Component is sometimes present in the complex, e.g., YajC (Törnroth-Horsefield et al, 2007) or AcrZ (Hobbs et al, 2012). The upper half of the periplasmic extension takes the form of an α-barrel domain (Calladine et al, 2001), while in the lower half this is an arrangement of coiled-coil hairpins – each subunit contributing two pairs of helices This arises from the fact that each of the TolC protomers is itself a product of internal gene duplication, manifesting as a structural repeat, which effectively gives the TolC trimer a pseudo-sixfold symmetry. Periplasmic adaptor proteins successfully recognize and couple a limited set of OMFs to a diverse range of transporters, with high fidelity and selectivity of assembly How they achieve this is one of the last remaining questions in the structure of efflux pumps. To avoid confusion we will use the alternative term “PAPs.”
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