The lysosomal polypeptide transporter TAPL: more than a housekeeping factor?

2011 ◽  
Vol 392 (1-2) ◽  
Author(s):  
Irina Bangert ◽  
Franz Tumulka ◽  
Rupert Abele
Keyword(s):  
Substrate Specificity ◽  
Adaptive Immunity ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Antigen Processing ◽  
Atp Hydrolysis ◽  
Phylogenetic Distribution ◽  
Physiological Functions ◽  
The Family

AbstractThe transporter associated with antigen processing-like (TAPL) is a polypeptide transporter translocating cytosolic peptides into the lumen of lysosomes driven by ATP hydrolysis. TAPL belongs to the family of ABC transporters and forms a homodimer. This ABC transporter not only shows a broad tissue but also a wide phylogenetic distribution, because orthologs are still found in nematodes and insects. Here, we present the topology, substrate specificity, and distribution of this intracellular polypeptide transporter. Additionally, we will discuss its proposed physiological functions such as housekeeping together with a specialized factor for metabolite storage as well as for the adaptive immunity.

scholarly journals A single power stroke by ATP binding drives substrate translocation in a heterodimeric ABC transporter

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Erich Stefan ◽  
Susanne Hofmann ◽  
Robert Tampé
Keyword(s):  
Abc Transporter ◽  
Antigen Processing ◽  
Atp Hydrolysis ◽  
Power Stroke ◽  
Atp Binding ◽  
Nucleotide Exchange ◽  
Single Turnover ◽  
Physiological Processes ◽  
Chemomechanical Coupling ◽  
Functional Homolog

ATP-binding cassette (ABC) transporters constitute the largest family of primary active transporters, responsible for many physiological processes and human maladies. However, the mechanism how chemical energy of ATP facilitates translocation of chemically diverse compounds across membranes is poorly understood. Here, we advance the quantitative mechanistic understanding of the heterodimeric ABC transporter TmrAB, a functional homolog of the transporter associated with antigen processing (TAP) by single-turnover analyses at single-liposome resolution. We reveal that a single conformational switch by ATP binding drives unidirectional substrate translocation. After this power stroke, ATP hydrolysis and phosphate release launch the return to the resting state, which facilitates nucleotide exchange and a new round of substrate binding and translocation. In contrast to hitherto existing steady-state assays, our single-turnover approach uncovers the power stroke in substrate translocation and the tight chemomechanical coupling in these molecular machines.

scholarly journals Insect ATP-Binding Cassette (ABC) Transporters: Roles in Xenobiotic Detoxification and Bt Insecticidal Activity

2019 ◽  
Vol 20 (11) ◽  
pp. 2829 ◽  
Author(s):  
Chao Wu ◽  
Swapan Chakrabarty ◽  
Minghui Jin ◽  
Kaiyu Liu ◽  
Yutao Xiao
Keyword(s):  
Abc Transporter ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Insecticidal Activity ◽  
Atp Hydrolysis ◽  
Atp Binding ◽  
Bt Toxin ◽  
Xenobiotic Detoxification ◽  
Binding Domains ◽  
Atp Binding Cassette

ATP-binding cassette (ABC) transporters, a large class of transmembrane proteins, are widely found in organisms and play an important role in the transport of xenobiotics. Insect ABC transporters are involved in insecticide detoxification and Bacillus thuringiensis (Bt) toxin perforation. The complete ABC transporter is composed of two hydrophobic transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). Conformational changes that are needed for their action are mediated by ATP hydrolysis. According to the similarity among their sequences and organization of conserved ATP-binding cassette domains, insect ABC transporters have been divided into eight subfamilies (ABCA–ABCH). This review describes the functions and mechanisms of ABC transporters in insecticide detoxification, plant toxic secondary metabolites transport and insecticidal activity of Bt toxin. With improved understanding of the role and mechanisms of ABC transporter in resistance to insecticides and Bt toxins, we can identify valuable target sites for developing new strategies to control pests and manage resistance and achieve green pest control.

scholarly journals Peroxisomal ABC transporters: functions and mechanism

2015 ◽  
Vol 43 (5) ◽  
pp. 959-965 ◽  
Author(s):  
Alison Baker ◽  
David J. Carrier ◽  
Theresia Schaedler ◽  
Hans R. Waterham ◽  
Carlo W. van Roermund ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Substrate Specificity ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Environmental Conditions ◽  
Developmental Stages ◽  
General Mechanism ◽  
Metabolic Functions ◽  
Single Entry ◽  
Oxidation Substrates

Peroxisomes are arguably the most biochemically versatile of all eukaryotic organelles. Their metabolic functions vary between different organisms, between different tissue types of the same organism and even between different developmental stages or in response to changed environmental conditions. New functions for peroxisomes are still being discovered and their importance is underscored by the severe phenotypes that can arise as a result of peroxisome dysfunction. The β-oxidation pathway is central to peroxisomal metabolism, but the substrates processed are very diverse, reflecting the diversity of peroxisomes across species. Substrates for β-oxidation enter peroxisomes via ATP-binding cassette (ABC) transporters of subfamily D; (ABCD) and are activated by specific acyl CoA synthetases for further metabolism. Humans have three peroxisomal ABCD family members, which are half transporters that homodimerize and have distinct but partially overlapping substrate specificity; Saccharomyces cerevisiae has two half transporters that heterodimerize and plants have a single peroxisomal ABC transporter that is a fused heterodimer and which appears to be the single entry point into peroxisomes for a very wide variety of β-oxidation substrates. Our studies suggest that the Arabidopsis peroxisomal ABC transporter AtABCD1 accepts acyl CoA substrates, cleaves them before or during transport followed by reactivation by peroxisomal synthetases. We propose that this is a general mechanism to provide specificity to this class of transporters and by which amphipathic compounds are moved across peroxisome membranes.

scholarly journals Structure of MlaFB uncovers novel mechanisms of ABC transporter regulation

2020 ◽  
Author(s):  
Ljuvica Kolich ◽  
Ya-Ting Chang ◽  
Nicolas Coudray ◽  
Sabrina I. Giacometti ◽  
Mark R. MacRae ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Atp Hydrolysis ◽  
Nucleotide Binding ◽  
Binding Domain ◽  
Regulatory Subunit ◽  
Nucleotide Binding Domain ◽  
Transporter Family ◽  
Bacterial Lipid ◽  
Phospholipid Transport

ABC transporters facilitate the movement of a diverse array of molecules across cellular membranes, using power from ATP hydrolysis. While the overall mechanism of the transport cycle has been characterized in detail for several important members of this transporter family, it is less well understood how the activity of ABC transporters is regulated in the cell post-translationally. Here we report the X-ray crystal structure of MlaFB from E. coli, an ABC nucleotide binding domain (MlaF) in complex with its putative regulatory subunit (MlaB). MlaFB constitutes the cytoplasmic portion of the larger MlaFEDB ABC transporter complex, which drives phospholipid transport across the bacterial envelope and is important for maintaining the integrity of the outer membrane barrier. Our data show that the regulatory subunit MlaB, a STAS domain protein, binds to the nucleotide binding domain and is required for its stability. Our structure also implicates a unique C-terminal tail of the ABC subunit, MlaF, in self-dimerization. Both the C-terminal tail of MlaF and the interaction with MlaB are required for the proper assembly of the MlaFEDB complex and its function in cells. This work leads to a new model for how the activity of an important bacterial lipid transporter may be regulated by small binding proteins, and raises the possibility that similar regulatory mechanisms may exist more broadly across the ABC transporter family, from bacteria to humans.

scholarly journals Distinct allosteric mechanisms of first-generation MsbA inhibitors

2021 ◽  
Author(s):  
Francois A Thelot ◽  
Wenyi Zhang ◽  
KangKang Song ◽  
Chen Xu ◽  
Jing Huang ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Drug Targets ◽  
Rational Design ◽  
First Generation ◽  
Atp Hydrolysis ◽  
Conformational Transition ◽  
Structural Data ◽  
Atpase Inhibitor ◽  
Binding Domains

Present in all kingdoms of life, ATP-binding cassette (ABC) transporters couple ATP hydrolysis to mechanical force and facilitate trafficking of diverse substrates across biological membranes. Although many ABC transporters are promising drug targets, their mechanisms of regulation by small molecule inhibitors remain largely unknown. Herein, we used the lipopolysaccharide (LPS) flippase MsbA, a prototypical ABC exporter, as a model system to probe mechanisms of allosteric modulation by compounds binding to the transmembrane domains (TMDs). Recent chemical screens have identified intriguing LPS transport inhibitors targeting MsbA: the ATPase stimulator TBT1 and the ATPase inhibitor G247. Despite preliminary biochemical and structural data, it is unclear how TBT1 and G247 bind to the MsbA TMDs yet induce opposite allosteric effect in the nucleotide-binding domains (NBDs). Through single-particle EM, mutagenesis and activity assay, we show that TBT1 and G247 bind adjacent yet separate locations in the TMDs, inducing drastic changes in TMD conformation and NBD positioning. Two TBT1 molecules asymmetrically occupy the LPS binding site to break the symmetry of MsbA, resulting in disordered transmembrane helices and decreased NBD distance. In this novel inhibited ABC transporter state, decreased distance between the NBDs causes stimulation of ATP hydrolysis yet LPS transport blockage. In contrast, G247 acts as a TMDs wedge, symmetrically increasing NBD separation and preventing conformational transition of MsbA. Our study uncovers the distinct mechanisms of the first-generation MsbA-specific inhibitors and demonstrates that rational design of substrate-mimicking compounds can be exploited to develop useful ABC transporter modulators.

Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics

2019 ◽  
Vol 26 (7) ◽  
pp. 1185-1223 ◽  
Author(s):  
Carolina I. Ghanem ◽  
Jose E. Manautou
Keyword(s):  
Abc Transporters ◽  
Basolateral Membrane ◽  
Clinical Use ◽  
Nucleotide Analogs ◽  
Synthetic Drugs ◽  
The Family ◽  
Hepatic Transporter ◽  
Related Proteins ◽  
Drug Pharmacokinetics ◽  
Conjugated Metabolites

Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.

scholarly journals Not Just Transporters: Alternative Functions of ABC Transporters in Bacillus subtilis and Listeria monocytogenes

2021 ◽  
Vol 9 (1) ◽  
pp. 163
Author(s):  
Jeanine Rismondo ◽  
Lisa Maria Schulz
Keyword(s):  
Bacillus Subtilis ◽  
Listeria Monocytogenes ◽  
Abc Transporters ◽  
Organic Molecules ◽  
Atp Hydrolysis ◽  
The Past ◽  
Wide Range ◽  
Regulatory Functions ◽  
Complex Organic ◽  
Detoxification Mechanisms

ATP-binding cassette (ABC) transporters are usually involved in the translocation of their cognate substrates, which is driven by ATP hydrolysis. Typically, these transporters are required for the import or export of a wide range of substrates such as sugars, ions and complex organic molecules. ABC exporters can also be involved in the export of toxic compounds such as antibiotics. However, recent studies revealed alternative detoxification mechanisms of ABC transporters. For instance, the ABC transporter BceAB of Bacillus subtilis seems to confer resistance to bacitracin via target protection. In addition, several transporters with functions other than substrate export or import have been identified in the past. Here, we provide an overview of recent findings on ABC transporters of the Gram-positive organisms B. subtilis and Listeria monocytogenes with transport or regulatory functions affecting antibiotic resistance, cell wall biosynthesis, cell division and sporulation.

Regional variations in ABC transporter expression along the mouse intestinal tract

2004 ◽  
Vol 17 (1) ◽  
pp. 11-20 ◽  
Author(s):  
David M. Mutch ◽  
Pascale Anderle ◽  
Muriel Fiaux ◽  
Robert Mansourian ◽  
Karine Vidal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Abc Transporter ◽  
Expression Profile ◽  
Abc Transporters ◽  
Intestinal Tract ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Assessment Model ◽  
Differentially Expressed ◽  
Distal Intestine

The ATP-binding cassette (ABC) family of proteins comprise a group of membrane transporters involved in the transport of a wide variety of compounds, such as xenobiotics, vitamins, lipids, amino acids, and carbohydrates. Determining their regional expression patterns along the intestinal tract will further characterize their transport functions in the gut. The mRNA expression levels of murine ABC transporters in the duodenum, jejunum, ileum, and colon were examined using the Affymetrix MuU74v2 GeneChip set. Eight ABC transporters (Abcb2, Abcb3, Abcb9, Abcc3, Abcc6, Abcd1, Abcg5, and Abcg8) displayed significant differential gene expression along the intestinal tract, as determined by two statistical models (a global error assessment model and a classic ANOVA, both with a P < 0.01). Concordance with semiquantitative real-time PCR was high. Analyzing the promoters of the differentially expressed ABC transporters did not identify common transcriptional motifs between family members or with other genes; however, the expression profile for Abcb9 was highly correlated with fibulin-1, and both genes share a common complex promoter model involving the NFκB, zinc binding protein factor (ZBPF), GC-box factors SP1/GC (SP1F), and early growth response factor (EGRF) transcription binding motifs. The cellular location of another of the differentially expressed ABC transporters, Abcc3, was examined by immunohistochemistry. Staining revealed that the protein is consistently expressed in the basolateral compartment of enterocytes along the anterior-posterior axis of the intestine. Furthermore, the intensity of the staining pattern is concordant with the expression profile. This agrees with previous findings in which the mRNA, protein, and transport function of Abcc3 were increased in the rat distal intestine. These data reveal regional differences in gene expression profiles along the intestinal tract and demonstrate that a complete understanding of intestinal ABC transporter function can only be achieved by examining the physiologically distinct regions of the gut.

Sign in / Sign up

Export Citation Format

Share Document