Hubacek institute for clinical and experimental medicine, laboratory for atherosclerosis research, center for experimental cardiovascular research, prague, czech republic received march 16, 2003 accepted june 20, 2003 summary. Probing of multidrug abc membrane transporters of single. In considering the transport of drugs, pharmacologists generally focus on transporters from two major superfamilies, abc atp binding cassette and slc solute carrier transporters most abc. One class of these permeases, known as multidrug resistance atp binding cassette abc transporters, translocate these molecules by coupling druglipid efflux with energy derived from the hydrolysis of atp. Another abc transporter is the breast cancer resistance protein bcrp, a member of the abcg transporter subfamily that partially overlaps the substrate specificity of pgp and mrps, conferring resistance to mitoxantrone, methotrexate, topotecan, and sn38. Structure and function of abc transporters physiology. Atpbinding cassette abc transporters are membranebound molecular pumps that form one of the largest of all protein families. By contrast, the transmembrane domains that create the translocation pathway are. One class of these permeases, known as multidrug resistance atp binding cassette abc transporters, translocate these molecules by coupling druglipid efflux with energy derived from the hydrolysis of. Abc transporters, ptype atpases and the solute carrier family slc.
Here we report the crystal structure of an nbd, fbpc, from the neisseria gonorrhoeae ferric iron uptake transporter with an unusual and substantial domain swap in the cterminal regulatory domain. Abc transporters are now known to be involved in the export of representatives from all of the major classes of cell surface glycoconjugates. Atpbinding cassette abc transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the atppowered translocation of many substrates across membranes. The 14 currently available structures of abc transporters have greatly advanced insight into the transport mechanism and revealed a tremendous structural diversity. Structural diversity of abc transporters journal of. Abc transporters are primary active transporters, which transport a. They invariably consist of two membranespanning domains that harbor a translocation pathway for a specific substrate, and two attached, waterexposed, and wellconserved atpbinding cassettes hence abc that power. The structures of the binding proteins for abc transporters vary in the topological threading between domains 4446. The mechanism by which nucleotidebinding domains nbds of abc transporters power the transport of substrates across cell membranes is currently unclear. Conformational motion of the abc transporter msba induced by atp hydrolysis peter p. Structure and mechanism of abc transporters fprime. Rees 1,2, eric johnson 1,2, and oded lewinson 2 1 howard hughes medical institute, california institute of technology, pasadena, ca 91125, usa. Several of them are central to phenomena of biomedical. It recognizes a variety of substrates and undergoes conformational changes to.
Special issue physiological and pathological roles of abc. The nbds, whose primary sequence is highly conserved throughout the superfamily, bind and hydrolyse atp to power the transport cycle. Recent structural advances with prokaryotic abc transporters have provided a qual. Pyrethroid resistance has become the largest unique obstacle for mosquito control worldwide. Paat, a novel atpase and transregulator of mitochondrial. The abc transporters not only move a variety of substrates into and out of the cell, but also are also involved in intracellular compartmental transport. The proposed mechanism is likely relevant for all abc transporters and might have implications also for other ntpases, thus representing a key step towards. Structure, dynamics, and energetics of atp hydrolysis by abc transporters a denosine triphosphate atpbinding cassette transporters abc transporters are transmembrane proteins present in cells. The hepatocyte nuclear factors, hnf1a and hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineagedetermining transcription factors in the kidney proximal tubule pt martovetsky et. Atpbinding cassette abc transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the atppowered translocation of many substrates across. Atpdependent substrate transport by the abc transporter msba is. For prokaryotic abc transporters that function as importers, substrate translocation is also dependent on another protein component, a high affinity binding protein that specifically associates with the ligand in the periplasm for delivery to the appropriate abc transporter 15 fig. There are, for example, 28 in saccharomyces,58 in caenorhabditis, 51 in drosophila,129 in arabadopsis,and the 69 abc transporters in e. Insights into how nucleotidebinding domains power abc.
Atp binding cassette abc transporters constitute a ubiquitous superfamily of integral. Dec 06, 2016 our teaser from a cycle the life of scientists illustrating work of researchers in oncology drug resistance mechanisms abc transporters, pglycoprotein. Atpbinding cassette abc transporters form a large superfamily of atpdependent protein complexes that mediate transport of a vast array of substrates across membranes. Sansom msp 2010 asymmetric switching in a homodimeric abc transporter. Atpbinding cassette abc transporters are implicated in a diverse range of physiological and pathophysiological processes, such as cholesterol and lipid transportation and multidrug resistance. Abc transporters use the energy of atp hydrolysis to transport substrates across cell membranes. Is atp hydrolysis the power stroke in abc transporters. Intro all organisms depend on membrane transport, whether. Structural similarities support a common mechanism by which abc. Currently, molecular mechanisms of multidrug abc atpbinding cassette membrane transporters remain elusive. The work by oldham and chen focuses on defining a specific facet of mechanism certain to be common to all abc transporters, namely, the chemical reaction. At the sequence level, the superfamily of abc transporters is identified by a characteristic set of highly conserved motifs.
Atp binding cassette abc transporters are found in all species and many species have lots. A blastp analysis revealed that crcds1 belongs to the abc transporter superfamily and shares 4050% sequence identity and 6270% sequence similarity with half. Abc transporters form the largest of all transporter families, and their structural study has made tremendous progress over recent years. Studies of other abc transporters, such as abcc7 or abcc1 could help our understanding of. Several of them are central to phenomena of biomedical interest, including cystic fibrosis and resistance to chemotherapeutic drugs. Borbat1, kavitha surendhran2, marco bortolus2, ping zou2, jack h. Abc transporters with similar mechanisms include bacterial permeases that pump nutrients into the cell, and tap1 and tap2 that pump peptide fragments of antigenic proteins into the lumen of the. Abc transporters have a characteristic architecture, which consists minimally of four domains fig.
Membrane transporters can be also divided into three main classes. The work by oldham and chen focuses on defining a specific facet of mechanism certain to be common to all abc transporters, namely, the chemical reaction mechanism of atp hydrolysis. Studies of other abc transporters, such as abcc7 or abcc1 could help our understanding of what abcc6 exact function is. Atpbinding cassette abc transporters constitute a ubiquitous superfamily of. The substrates that can be transported include ions, amino acids, peptides, sugars, and other molecules that are mostly hydrophilic.
The highly conserved abc domains of abc transporters provide the nucleotidedependent engine that drives transport. Abc transporters are defined by several highly conserved consensus amino acid sequences within the nbds. Jun 11, 2010 currently, molecular mechanisms of multidrug abc atpbinding cassette membrane transporters remain elusive. Comparison of mechanistic transport cycle models of abc exporters. Atp binds to the a subunits and it is then hydrolyzed to power the alternation, but the exact. Abca4, also known as abcr, is a 250 kda singlechain abc transporter localized to the disk margins of vertebrate photoreceptor outer segments. Another abc transporter is the breast cancer resistance protein bcrp, a member of the abcg transporter subfamily that partially overlaps the substrate specificity of pgp and mrps, conferring. The hepatocyte nuclear factors, hnf1a and hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineagedetermining transcription.
The tmds, whose primary sequence and protein fold can be quite. Abc transporters play a crucial role in the development of resistance by the efflux of anticancer agents outside of cancer cells. Structure, dynamics, and energetics of atp hydrolysis by abc transporters a denosine triphosphate atpbinding cassette transporters abc transporters are transmembrane proteins present in cells of every living organism. Early biochemical studies on bacterial nutrient import systems revealed a class of multisubunit transporters that all contained an essential cytoplasmic factor with atp. The role of abc transporters in progression and clinical outcome of colorectal cancer i. Abc transporters involved in export of cell surface. The prototypical abc transporter consists of four domains.
The abc transporters are asymmetrically distributed when they are present in the same. It is represented in all extant phyla, from prokaryotes to humans abc transporters often consist of multiple subunits, one or two of which are transmembrane proteins and one or two of which are membraneassociated aaa atpases. Abc transporters are thought to be associated with pyrethroid resistance in some agricultural pests, but little information is known for mosquitoes. Oct 01, 2002 atpbinding cassette abc transporters are membranebound molecular pumps that form one of the largest of all protein families. Bacterial abc transporters are essential in cell viability, virulence, and pathogenicity. For many other abc transporters, it has also been demonstrated that substrate binding to the tmds induces a conformational change in the.
Pdf atpbinding cassette abc transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the. Overlapping functions of abc transporters in topotecan. Subsequently, abc transporters were identified in the assembly of teichoic acid in bacillus subtilis 168 and in the protein glycosylation system from campylobacter jejuni. Atpbinding cassette abc transporters are responsible for the atppowered translocation of many substrates across membranes. The atpbinding cassette transporters abc transporters are a transport system superfamily. Structure, dynamics, and energetics of atp hydrolysis by. Abc transporters now form the largest family of membranespanning transport proteins, ubiquitous in all branches of life 1. However, the mechanism by which abcc6 dysfunction causes diminished atp release remains an enigma. Nov 18, 2012 types of membrane transporters 8 2000 genes in the human genome 7% of the total number of genes code for transporters or transporterrelated proteins. Atpbinding cassette abc transporters are ubiquitous integral membrane proteins that facilitate the transbilayer movement of ligands.
Asymmetric switching in a homodimeric abc transporter. Abc transporter proteins definition of abc transporter. It is established that efflux transporters of the atpbinding cassette abc superfamily can affect the pharmacokinetics of drugs through mechanisms pertaining to drug absorption, elimination. Abc transporters are a large family of membrane proteins involved in a variety of cellular processes, including multidrug and tumor resistance and ion channel regulation. Abc transporters share a common architecture comprising two hydrophilic nucleotidebinding domains nbds and two hydrophobic. Mutations in the gene that codes for one of these abc transporter proteins is believed to be responsible for cystic fibrosis. The atpbinding cassette transporters abc transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. Covalent inhibitors of pglycoprotein atpase activity. Recent structural advances with prokaryotic abc transporters have provided a qualitative molecular framework for deciphering the transport cycle. Types of membrane transporters 8 2000 genes in the human genome 7% of the total number of genes code for transporters or transporterrelated proteins. The overall free energy change associated with the reaction is positive, suggesting that atp hydrolysis itself does not provide the power stroke for substrate transport in btucdf. Dynamics of a bacterial multidrug abc transporter in the. Data and a hypothesis on the possible roles of abcc6 in acquired metabolic diseases are also discussed.
An inwardfacing conformation of a putative metalchelate. The atpbinding cassette abc transporters family is one of the largest families of membrane proteins existing in all living organisms. Abc transporters are primary active transporters, which transport a wide range of substrates mainly to the outside of a cell membrane or organelle. Over four decades of investigations into abc transporters have revealed numerous. In addition to the sequence comparisons of the abc domains, there are also hints from the structures of the binding proteins that the haa and mos branch could exhibit a distinct tmd fold.
Abc transporters are ubiquitous and clinically important. Some substrates of abc transporters are membrane bound. In this study, we synthesized and characterized purified spherically shaped silver nanoparticles ag nps 11. As more amino acid sequence information became available, it was recognized that the primary structure of the atpbinding domains of these transporters was. I will focus on a brief overview of the structure and function of abc transporters, and leave the details of proposed mechanisms for a different day and a different answer. Abstract atpbinding cassette transporters abc transporters utilize the energy of atp hydrolysis to translocate an unusually diverse set of substrates across cellular membranes. All abc transporters contain two membranespanning domains that harbor a translocation pathway for a specific substrate. Abc transporters with similar mechanisms include bacterial permeases that pump nutrients into the cell, and tap1 and tap2 that pump peptide fragments of antigenic proteins into the lumen of the endoplasmic reticulum. A novel missense mutation in abca1 results in altered protein trafficking and reduced phosphatidylserine translocation. Energy derived from the hydrolysis of atp is used to transport the substrate across the membrane against a concentration gradient.
Atpbinding cassette abc transporters in human metabolism and diseases j. An important goal is to develop quantitative models. An important goal is to develop quantitative models that detail the kinetic and molecular mechanisms by which abc transporters couple the binding and hydrolysis of atp to substrate translocation. They invariably consist of two membranespanning domains that harbor a translo. Gary pilarchik the rusted garden recommended for you. Kidney versus liver specification of slc and abc drug. However, the use of immunohistochemical analysis is semi.
1063 908 187 942 292 463 1242 198 1326 560 1075 962 1365 1241 914 679 1319 1091 852 1138 744 1196 500 881 87 501 414 369 1256 1475 790 703 202 1119 301 1434 1165 631 609 701 882 1332 729 409