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Microbiology (Reading, England) Nov 2022ATP-binding cassette (ABC) transporters are one of the largest protein superfamilies and are found in all living organisms. These transporters use the energy from ATP... (Review)
Review
ATP-binding cassette (ABC) transporters are one of the largest protein superfamilies and are found in all living organisms. These transporters use the energy from ATP binding and hydrolysis to transport various substrates. In this review, we focus on the structural and functional aspects of ABC transporters, with special emphasis on type VII ABC transporters, a newly defined class possessing characteristic structures. A notable feature of type VII ABC transporters is that they assemble into tripartite complexes that span both the inner and outer membranes of Gram-negative bacteria. One of the original type VII ABC transporters, which possesses all characteristic features of this class, is the macrolide efflux transporter MacB. Recent structural analyses of MacB and homologue proteins revealed the unique mechanisms of substrate translocation by type VII ABC transporters.
Topics: ATP-Binding Cassette Transporters; Models, Molecular; Membrane Transport Proteins; Biological Transport; Adenosine Triphosphate
PubMed: 36409601
DOI: 10.1099/mic.0.001257 -
Molecular Microbiology Apr 2017Transporters are essential players in bacterial growth and survival, since they are key for uptake of nutrients on the one hand, and for defence against endogenous and... (Review)
Review
Transporters are essential players in bacterial growth and survival, since they are key for uptake of nutrients on the one hand, and for defence against endogenous and environmental stresses on the other hand. Remarkably, in addition to their primary role in substrate translocation, it has become clear that some transporters have acquired a secondary function as sensors and information processors in signalling pathways. In this review, we describe recent advances in our understanding of the role of transporters in such signalling cascades, and discuss some of the emergent dynamic behaviour found in hallmark examples. A particular focus is placed on new insights into mechanistic details of information transfer between transporters and regulatory proteins. Quantitative considerations reveal that these signalling complexes can implement a remarkable diversity of regulatory logic functions, where the transporter can act as activity switch, as positive or negative reporter of transport flux, or as a signalling hub for the integration of multiple inputs. Such a dual use of transport proteins not only enables efficient substrate translocation but is also an elegant strategy to integrate important information about the cell's external conditions with its current physiological state.
Topics: Bacterial Proteins; Carrier Proteins; Membrane Transport Proteins; Signal Transduction
PubMed: 28152228
DOI: 10.1111/mmi.13633 -
Journal of Structural Biology Dec 2021The flux of ions and molecules in and out of the cell is vital for maintaining the basis of various biological processes. The permeation of substrates across the... (Review)
Review
The flux of ions and molecules in and out of the cell is vital for maintaining the basis of various biological processes. The permeation of substrates across the cellular membrane is mediated through the function of specialized integral membrane proteins commonly known as membrane transporters. These proteins undergo a series of structural rearrangements that allow a primary substrate binding site to be accessed from either side of the membrane at a given time. Structural insights provided by experimentally resolved structures of membrane transporters have aided in the biophysical characterization of these important molecular drug targets. However, characterizing the transitions between conformational states remains challenging to achieve both experimentally and computationally. Though molecular dynamics simulations are a powerful approach to provide atomistic resolution of protein dynamics, a recurring challenge is its ability to efficiently obtain relevant timescales of large conformational transitions as exhibited in transporters. One approach to overcome this difficulty is to adaptively guide the simulation to favor exploration of the conformational landscape, otherwise known as adaptive sampling. Furthermore, such sampling is greatly benefited by the statistical analysis of Markov state models. Historically, the use of Markov state models has been effective in quantifying slow dynamics or long timescale behaviors such as protein folding. Here, we review recent implementations of adaptive sampling and Markov state models to not only address current limitations of molecular dynamics simulations, but to also highlight how Markov state modeling can be applied to investigate the structure-function mechanisms of large, complex membrane transporters.
Topics: Animals; Binding Sites; Cell Membrane; Humans; Markov Chains; Membrane Transport Proteins; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Thermodynamics
PubMed: 34600140
DOI: 10.1016/j.jsb.2021.107800 -
Biological Chemistry Feb 2017Solute carriers from the SLC4, SLC23, and SLC26 families are involved in pH regulation, vitamin C transport and ion homeostasis. While these families do not share any... (Review)
Review
Solute carriers from the SLC4, SLC23, and SLC26 families are involved in pH regulation, vitamin C transport and ion homeostasis. While these families do not share any obvious sequence relationship, they are united by their unique and novel architecture. Each member of this structural class is organized into two structurally related halves of seven transmembrane segments each. These halves span the membrane with opposite orientations and form an intricately intertwined structure of two inverted repeats. This review highlights the general design principles of this fold and reveals the diversity between the different families. We discuss their domain architecture, structural framework and transport mode and detail an initial transport mechanism for this fold inferred from the recently solved structures of different members.
Topics: Animals; Biological Transport; Cell Membrane; Humans; Membrane Transport Proteins; Protein Domains; Protein Multimerization; Repetitive Sequences, Amino Acid
PubMed: 27865089
DOI: 10.1515/hsz-2016-0254 -
ACS Infectious Diseases Feb 2024is a commensal of the human upper respiratory tract that can infect diverse host niches due, at least in part, to its ability to withstand both endogenous and...
is a commensal of the human upper respiratory tract that can infect diverse host niches due, at least in part, to its ability to withstand both endogenous and host-mediated oxidative stresses. Here, we show that , a gene previously linked to iron import, is essential for manganese recruitment the HfeBCD transporter. Structural analyses show that metal binding in HfeA uses a unique mechanism that involves substantial rotation of the C-terminal lobe of the protein. Disruption of reduced manganese acquisition and was associated with decreased growth under aerobic conditions, impaired manganese-superoxide dismutase activity, reduced survival in macrophages, and changes in biofilm production in the presence of superoxide. Collectively, this work shows that HfeA contributes to manganese acquisition and virulence attributes. High conservation of the permease in species suggests that it may serve similar roles in other pathogenic Pasteurellaceae.
Topics: Humans; Haemophilus influenzae; Membrane Transport Proteins; Manganese; Biofilms; Homeostasis
PubMed: 38240689
DOI: 10.1021/acsinfecdis.3c00407 -
Pflugers Archiv : European Journal of... Feb 2016Solute carriers (SLCs) are one of the largest groups of multi-spanning membrane proteins in mammals and include ubiquitously expressed proteins as well as proteins with... (Review)
Review
Solute carriers (SLCs) are one of the largest groups of multi-spanning membrane proteins in mammals and include ubiquitously expressed proteins as well as proteins with highly restricted tissue expression. A vast number of studies have addressed the function and organization of SLCs as well as their posttranslational regulation, but only relatively little is known about the role of SLC glycosylation. Glycosylation is one of the most abundant posttranslational modifications of animal proteins and through recent advances in our understanding of protein-glycan interactions, the functional roles of SLC glycosylation are slowly emerging. The purpose of this review is to provide a concise overview of the aspects of glycobiology most relevant to SLCs, to discuss the roles of glycosylation in the regulation and function of SLCs, and to outline the major open questions in this field, which can now be addressed given major technical advances in this and related fields of study in recent years.
Topics: Animals; Glycosylation; Humans; Membrane Transport Proteins; Polysaccharides; Protein Processing, Post-Translational
PubMed: 26383868
DOI: 10.1007/s00424-015-1730-4 -
Biochemical Society Transactions Feb 2019Oligomerisation is a key feature of integral membrane transporters with roles in structure, function and stability. In this review, we cover some very recent advances in... (Review)
Review
Oligomerisation is a key feature of integral membrane transporters with roles in structure, function and stability. In this review, we cover some very recent advances in our understanding of how oligomerisation affects these key transporter features, with emphasis on a few groups of transporters, including the nucleobase ascorbate transporters, neurotransmitter sodium symporters and major facilitator superfamily members.
Topics: Ascorbic Acid; Membrane Transport Proteins; Neurotransmitter Agents; Polymerization
PubMed: 30578344
DOI: 10.1042/BST20180316 -
Research in Microbiology 2018Efflux pumps are membrane proteins which contribute to multi-drug resistance. In Gram-negative bacteria, some of these pumps form complex tripartite assemblies in... (Review)
Review
Efflux pumps are membrane proteins which contribute to multi-drug resistance. In Gram-negative bacteria, some of these pumps form complex tripartite assemblies in association with an outer membrane channel and a periplasmic membrane fusion protein. These tripartite machineries span both membranes and the periplasmic space, and they extrude from the bacterium chemically diverse toxic substrates. In this chapter, we summarise current understanding of the structural architecture, functionality, and regulation of tripartite multi-drug efflux assemblies.
Topics: Bacterial Proteins; Gram-Negative Bacteria; Membrane Transport Proteins; Models, Molecular; Protein Conformation
PubMed: 29787834
DOI: 10.1016/j.resmic.2018.05.003 -
Protein Science : a Publication of the... Oct 2015Major facilitator superfamily (MFS) is a large class of secondary active transporters widely expressed across all life kingdoms. Although a common 12-transmembrane... (Review)
Review
Major facilitator superfamily (MFS) is a large class of secondary active transporters widely expressed across all life kingdoms. Although a common 12-transmembrane helix-bundle architecture is found in most MFS crystal structures available, a common mechanism of energy coupling remains to be elucidated. Here, we discuss several models for energy-coupling in the transport process of the transporters, largely based on currently available structures and the results of their biochemical analyses. Special attention is paid to the interaction between protonation and the negative-inside membrane potential. Also, functional roles of the conserved sequence motifs are discussed in the context of the 3D structures. We anticipate that in the near future, a unified picture of the functions of MFS transporters will emerge from the insights gained from studies of the common architectures and conserved motifs.
Topics: Binding Sites; Biological Transport; Crystallography, X-Ray; Energy Metabolism; Membrane Transport Proteins; Models, Biological; Protein Conformation
PubMed: 26234418
DOI: 10.1002/pro.2759 -
Trends in Biochemical Sciences Aug 2015SemiSWEETs and SWEETs have emerged as unique sugar transporters. First discovered in plants with the help of fluorescent biosensors, homologs exist in all kingdoms of... (Review)
Review
SemiSWEETs and SWEETs have emerged as unique sugar transporters. First discovered in plants with the help of fluorescent biosensors, homologs exist in all kingdoms of life. Bacterial and plant homologs transport hexoses and sucrose, whereas animal SWEETs transport glucose. Prokaryotic SemiSWEETs are small and comprise a parallel homodimer of an approximately 100 amino acid-long triple helix bundle (THB). Duplicated THBs are fused to create eukaryotic SWEETs in a parallel orientation via an inversion linker helix, producing a similar configuration to that of SemiSWEET dimers. Structures of four SemiSWEETs have been resolved in three states: open outside, occluded, and open inside, indicating alternating access. As we discuss here, these atomic structures provide a basis for exploring the evolution of structure-function relations in this new class of transporters.
Topics: Animals; Biological Transport; Hexoses; Humans; Membrane Transport Proteins; Models, Molecular; Protein Conformation
PubMed: 26071195
DOI: 10.1016/j.tibs.2015.05.005