Abstract
Tripartite efflux pumps and the related type 1 secretion systems (T1SSs) in Gram-negative organisms are diverse in function, energization, and structural organization. They form continuous conduits spanning both the inner and the outer membrane and are composed of three principal components—the energized inner membrane transporters (belonging to ABC, RND, and MFS families), the outer membrane factor channel-like proteins, and linking the two, the periplasmic adaptor proteins (PAPs), also known as the membrane fusion proteins (MFPs). In this review we summarize the recent advances in understanding of structural biology, function, and regulation of these systems, highlighting the previously undescribed role of PAPs in providing a common architectural scaffold across diverse families of transporters. Despite being built from a limited number of basic structural domains, these complexes present a staggering variety of architectures. While key insights have been derived from the RND transporter systems, a closer inspection of the operation and structural organization of different tripartite systems reveals unexpected analogies between them, including those formed around MFS- and ATP-driven transporters, suggesting that they operate around basic common principles. Based on that we are proposing a new integrated model of PAP-mediated communication within the conformational cycling of tripartite systems, which could be expanded to other types of assemblies.
Highlights
THE PROBLEM OF PUMPING ACROSS TWO MEMBRANES IN GRAM-NEGATIVE BACTERIAThe cell envelope of Gram-negative bacteria consists of three fundamental layers: the inner or cytoplasmic membrane, the peptidoglycan cell wall, and the outer membrane
Subsequent bioinformatic analysis of the available periplasmic adaptor proteins (PAPs) suggested that they form a novel, clearly defined group, which was ascribed “membrane fusion” capability, based on the superficial resemblance of hairpin domain architecture to the coiled-coil domains observed in bona f ide membrane fusion proteins, e.g., paramyxoviral SV5.722 This inferred fusion function has never been demonstrated in any PAP since; the old-name association still persists, and they are sometimes referred to in the literature as “membrane fusion proteins” or MFPs
We further suggest that the rearrangement of the Periplasmic Core Domains (PCDs) and the transmembrane domains (TMDs) of the transporter is sensed by the membrane proximal domain (MPD) and transmembrane helices (TMs)-domains of the PAPs, providing additional allosteric signaling
Summary
Topology and Structural Organization of MacB Family Members 5.7.4. General Topology of MacB/FtsX Family and TM Domains 5.7.5. Relations of the Membrane Porter Domains of MacB/FtsX to Other ABC Transporter Families 5.7.8. Gates within the OMFs: Outer Membrane Loops 6.3.2. Domain Organization of the PAPs Associated with RND and MacB-Assemblies 7.4. PAPs Associated with MFS Transporters and T1SS 7.5. PAPs Associated with the Heavy Metal Efflux (HME) Family pubs.acs.org/CR. 8. Assembly and Function of the RND-Based Tripartite Complexes 8.1. RND−PAP Interface: Structural Data Suggests Asymmetry of the Assembled Tripartite Assembly and Different Roles for the PAPs 8.4. Functional Assays in Artificial Membrane Environments Provide Additional Insights into the Regulation of the RND Transporters and the Role of the Lipid Environments.
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