The Evolutionary Repertoires of the Eukaryotic-Type ABC Transporters in Terms of the Phylogeny of ATP-binding Domains in Eukaryotes and Prokaryotes

Abstract ATP-binding cassette (ABC) transporters are essential proteins that are found across all kingdoms of life. ABC transporters harness the energy of ATP hydrolysis to drive the import of nutrients inside bacterial cells or the export of toxic compounds or essential lipids across bacteria and eukaryotic membranes. Typically, ABC transporters consist of transmembrane domains (TMDs) and nucleotide-binding domains (NBDs) to bind their substrate and ATP, respectively. The TMDs dictate what ligands can be recognised, whereas the NBDs are the power engine of the ABC transporter, carrying out ATP binding and hydrolysis. It has been proposed that they utilise the alternating access mechanism, inward- to outward-facing conformation, to transport their substrates. Here, we will review the recent progress on the structure determination of eukaryotic and bacterial ABC transporters as well as the novel mechanisms that have also been proposed, that fall out of the alternating access mechanism model.

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Inventory and analysis of ATP-binding cassette (ABC) systems inBrugia malayi

Parasitology ◽

10.1017/s0031182010000120 ◽

2010 ◽

Vol 137 (8) ◽

pp. 1195-1212 ◽

Cited By ~ 19

Author(s):

B. F. ARDELLI ◽

L. E. STITT ◽

J. B. TOMPKINS

Keyword(s):

Drug Resistance ◽

Dna Repair ◽

Abc Transporters ◽

Atp Binding ◽

Switch Region ◽

Linker Region ◽

Protein Superfamilies ◽

Binding Domains ◽

Reverse Transcription Pcr ◽

Signature Sequence

SUMMARYABC systems are one of the largest described protein superfamilies. These systems have a domain organization that may contain 1 or more transmembrane domains (ABC_TM1F) and 1 or 2 ATP-binding domains (ABC_2). The functions (e.g., import, export and DNA repair) of these proteins distinguish the 3 classes of ABC systems. Mining and PCR-based cloning were used to identify 33 putative ABC systems from theBrugia malayigenome. There were 31 class 2 genes, commonly called ABC transporters, and 2 class 3 genes. The ABC transporters were divided into subfamilies. Three belonged to subfamily A, 16 to subfamily B, 5 to subfamily C, 1 to subfamily E and 3 to subfamilies F and G, respectively. None were placed in subfamilies D and H. Similar to other ABC systems, the ABC_2 domain ofB. malayigenes was conserved and contained the Walker A and B motifs, the signature sequence/linker region and the switch region with the conserved histidine. The ABC_TM1F domain was less conserved. The relative abundance of ABC systems was quantified using real-time reverse transcription PCR and was significantly higher in female adults ofB. malayithan in males and microfilaria, particularly those in subfamilies B and C, which are associated with drug resistance.

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Structure and mechanism of ATP-binding cassette transporters

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2008.0125 ◽

2008 ◽

Vol 364 (1514) ◽

pp. 239-245 ◽

Cited By ~ 244

Author(s):

Kaspar P Locher

Keyword(s):

Abc Transporters ◽

Integral Membrane Proteins ◽

Atp Binding ◽

X Ray ◽

X Ray Crystallography ◽

Binding Domains ◽

Mechanistic Insight ◽

Future Challenges ◽

Hydrolysis Of ◽

Atp Binding Cassette

ATP-binding cassette (ABC) transporters constitute a large superfamily of integral membrane proteins that includes both importers and exporters. In recent years, several structures of complete ABC transporters have been determined by X-ray crystallography. These structures suggest a mechanism by which binding and hydrolysis of ATP by the cytoplasmic, nucleotide-binding domains control the conformation of the transmembrane domains and therefore which side of the membrane the translocation pathway is exposed to. A basic, conserved two-state mechanism can explain active transport of both ABC importers and ABC exporters, but various questions remain unresolved. In this article, I will review some of the crystal structures and the mechanistic insight gained from them. Future challenges for a better understanding of the mechanism of ABC transporters will be outlined.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20112829 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2829 ◽

Cited By ~ 9

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.

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Characterization of Oligomeric Human Half-ABC Transporter ATP-binding Cassette G2

Journal of Biological Chemistry ◽

10.1074/jbc.m310785200 ◽

2004 ◽

Vol 279 (19) ◽

pp. 19781-19789 ◽

Cited By ~ 178

Author(s):

Junkang Xu ◽

Yang Liu ◽

Youyun Yang ◽

Susan Bates ◽

Jian-Ting Zhang

Keyword(s):

Abc Transporters ◽

Transmembrane Domain ◽

Gel Filtration ◽

Nucleotide Binding ◽

Sucrose Density Gradient ◽

Atp Binding ◽

Cancer Resistance ◽

Binding Domains ◽

Resistance Protein ◽

Atp Binding Cassette

Human ATP-binding cassette G2 (ABCG2, also known as mitoxantrone resistance protein, breast cancer-resistance protein, ABC placenta) is a member of the superfamily of ATP-binding cassette (ABC) transporters that have a wide variety of substrates. Overexpression of human ABCG2 in model cancer cell lines causes multidrug resistance by actively effluxing anticancer drugs. Unlike most of the other ABC transporters which usually have two nucleotide-binding domains and two transmembrane domains, ABCG2 consists of only one nucleotide-binding domain followed by one transmembrane domain. Thus, ABCG2 has been thought to be a half-transporter that may function as a homodimer. In this study, we characterized the oligomeric feature of human ABCG2 using non-denaturing detergent perfluoro-octanoic acid and Triton X-100 in combination with gel filtration, sucrose density gradient sedimentation, and gel electrophoresis. Unexpectedly, we found that human ABCG2 exists mainly as a tetramer, with a possibility of a higher form of oligomerization. Monomeric and dimeric ABCG2 did not appear to be the major form of the protein. Further immunoprecipitation analysis showed that the oligomeric ABCG2 did not contain any other proteins. Taken together, we conclude that human ABCG2 likely exists and functions as a homotetramer.

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The Human ATP-Binding Cassette (ABC) Transporter Superfamily

10.22541/au.164001179.92800452/v1 ◽

2021 ◽

Author(s):

Michael Dean ◽

Karobi Moitra ◽

Rando Allikmets

Keyword(s):

Abc Transporter ◽

Abc Transporters ◽

Rare Variants ◽

Mendelian Inheritance ◽

Atp Binding ◽

Evolutionary Diversification ◽

Binding Domains ◽

Cholesterol Levels ◽

Human Disorders ◽

Atp Binding Cassette

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intra-cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. Common polymorphisms and rare variants in ABC genes are associated with several complex phenotypes such as gout, gallstones, and cholesterol levels. Overexpression or amplification of specific drug efflux genes contributes to chemotherapy multidrug resistance. Conservation of the ATP-binding domains of ABC transporters defines the superfamily members, and phylogenetic analysis groups the 48 human ABC transporters into seven distinct subfamilies. While the conservation of ABC genes across most vertebrate species is high, there is also considerable gene duplication, deletion, and evolutionary diversification.

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Combining Mutations That Inhibit Two Distinct Steps of the ATP Hydrolysis Cycle Restores Wild-Type Function in the Lipopolysaccharide Transporter and Shows that ATP Binding Triggers Transport

mBio ◽

10.1128/mbio.01931-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 4

Author(s):

Brent W. Simpson ◽

Karanbir S. Pahil ◽

Tristan W. Owens ◽

Emily A. Lundstedt ◽

Rebecca M. Davis ◽

...

Keyword(s):

Abc Transporter ◽

Conformational Changes ◽

Abc Transporters ◽

Atp Binding ◽

Gram Negative Bacteria ◽

Wild Type ◽

Lethal Effects ◽

Gram Negative ◽

Binding Domains ◽

Transport Cycle

ABSTRACT ATP-binding cassette (ABC) transporters constitute a large family of proteins present in all domains of life. They are powered by dynamic ATPases that harness energy from binding and hydrolyzing ATP through a cycle that involves the closing and reopening of their two ATP-binding domains. The LptB2FGC exporter is an essential ABC transporter that assembles lipopolysaccharides (LPS) on the surface of Gram-negative bacteria to form a permeability barrier against many antibiotics. LptB2FGC extracts newly synthesized LPS molecules from the inner membrane and powers their transport across the periplasm and through the outer membrane. How LptB2FGC functions remains poorly understood. Here, we show that the C-terminal domain of the dimeric LptB ATPase is essential for LPS transport in Escherichia coli. Specific changes in the C-terminal domain of LptB cause LPS transport defects that can be repaired by intragenic suppressors altering the ATP-binding domains. Surprisingly, we found that each of two lethal changes in the ATP-binding and C-terminal domains of LptB, when present in combined form, suppressed the defects associated with the other to restore LPS transport to wild-type levels both in vivo and in vitro. We present biochemical evidence explaining the effect that each of these mutations has on LptB function and how the observed cosuppression results from the opposing lethal effects these changes have on the dimerization state of the LptB ATPase. We therefore propose that these sites modulate the closing and reopening of the LptB dimer, providing insight into how the LptB2FGC transporter cycles to export LPS to the cell surface and how to inhibit this essential envelope biogenesis process. IMPORTANCE Gram-negative bacteria are naturally resistant to many antibiotics because their surface is covered by the glycolipid LPS. Newly synthesized LPS is transported across the cell envelope by the multiprotein Lpt machinery, which includes LptB2FGC, an unusual ABC transporter that extracts LPS from the inner membrane. Like in other ABC transporters, the LptB2FGC transport cycle is driven by the cyclical conformational changes that a cytoplasmic, dimeric ATPase, LptB, undergoes when binding and hydrolyzing ATP. How these conformational changes are controlled in ABC transporters is poorly understood. Here, we identified two lethal changes in LptB that, when combined, remarkably restore wild-type transport function. Biochemical studies revealed that the two changes affect different steps in the transport cycle, having opposing, lethal effects on LptB’s dimerization cycle. Our work provides mechanistic details about the LptB2FGC extractor that could be used to develop Lpt inhibitors that would overcome the innate antibiotic resistance of Gram-negative bacteria.

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How do ABC transporters drive transport?

Biological Chemistry ◽

10.1515/bc.2004.121 ◽

2004 ◽

Vol 385 (10) ◽

pp. 927-933 ◽

Cited By ~ 59

Author(s):

Chris Van Der Does ◽

Robert Tampé

Keyword(s):

High Resolution ◽

Membrane Proteins ◽

Crystal Structures ◽

Abc Transporters ◽

Nucleotide Binding ◽

Integral Membrane Proteins ◽

Biochemical Data ◽

Atp Binding ◽

Binding Domains ◽

Biochemical Level

Abstract Members of the ATP-binding cassette (ABC) superfamily are integral membrane proteins that hydrolyze ATP to drive transport. In the last two decades these proteins have been extensively characterized on a genetic and biochemical level, and in recent years high-resolution crystal structures of several nucleotide-binding domains and full-length transporters have extended our knowledge. Here we discuss the possible mechanisms of transport that have been derived from these crystal structures and the extensive available biochemical data.

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Functional Significance of the E Loop, a Novel Motif Conserved in the Lantibiotic Immunity ATP-Binding Cassette Transport Systems

Journal of Bacteriology ◽

10.1128/jb.00003-10 ◽

2010 ◽

Vol 192 (11) ◽

pp. 2801-2808 ◽

Cited By ~ 18

Author(s):

Ken-ichi Okuda ◽

Sae Yanagihara ◽

Tomomichi Sugayama ◽

Takeshi Zendo ◽

Jiro Nakayama ◽

...

Keyword(s):

Amino Acids ◽

Abc Transporters ◽

Amino Acid Replacement ◽

Transport Systems ◽

Atp Binding ◽

Transport Activity ◽

Multiple Sequence ◽

Binding Domains ◽

Alignment Analysis ◽

Atp Binding Cassette

ABSTRACT Lantibiotics are peptide-derived antibacterial substances produced by some Gram-positive bacteria and characterized by the presence of unusual amino acids, like lanthionines and dehydrated amino acids. Because lantibiotic producers may be attacked by self-produced lantibiotics, they express immunity proteins on the cytoplasmic membrane. An ATP-binding cassette (ABC) transport system mediated by the LanFEG protein complex is a major system in lantibiotic immunity. Multiple-sequence alignment analysis revealed that LanF proteins contain the E loop, a variant of the Q loop, which is a well-conserved motif in the nucleotide-binding domains (NBDs) of general ABC transporters. To elucidate E loop function, we introduced a mutation in the NukF protein, which is involved in the nukacin-ISK-1 immunity system. Amino acid replacement of glutamic acid in the E loop with glutamine (E85Q) resulted in slight decreases in the immunity level and transport activity. Additionally, the E85A mutation severely impaired the immunity level and transport activity. On the other hand, ATPase activities of purified E85Q and E85A mutants were almost similar to that of the wild type. These results suggested that the E loop found in ABC transporters involved in lantibiotic immunity plays a significant role in the function of these transporters, especially in the structural change of transmembrane domains.

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Growth Promotion and Increased ATP-Binding Cassette Transporters Expression by Liraglutide in Triple Negative Breast Cancer Cell Line MDA-MB-231

Drug Research ◽

10.1055/a-1345-7890 ◽

2021 ◽

Author(s):

Amir Shadboorestan ◽

Parastoo Tarighi ◽

Mahsa Koosha ◽

Homa Faghihi ◽

Mohammad Hossein Ghahremani ◽

...

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Triple Negative Breast Cancer ◽

Abc Transporters ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Growth Promotion ◽

Atp Binding ◽

Mesenchymal Transition ◽

Atp Binding Cassette

Background Glucagon-like petide-1 (GLP-1) agonists such as liraglutide are widely employed in type 2 diabetes due to their glucose reducing properties and small risk of hypoglycemia. Recently, it has been shown that GLP-1agonists can inhibit breast cancer cells growth. Nonetheless, concerns are remained about liraglutide tumor promoting effects as stated by population studies. Material and Methods We evaluated the effects liraglutide on proliferation of MDA-MB-231 cells by MTT assay and then ATP-binding cassette (ABC) transporters expressions assessed by Real time PCR. Statistical comparisons were made using one-way analysis of variance followed by a post hoc Dunnett test. Results Here, we report that liraglutide can stimulate the growth of highly invasive triple negative cell line MDA-MB-231; which can be attributed to AMPK-dependent epithelial-mesenchymal transition (EMT) happening in MDA-MB-231 context. Toxicity effects were only observed with concentrations far above the serum liraglutide concentration. ATP-binding cassette (ABC) transporters expressions were upregulated, indicating the possible drug resistance and increased EMT. Conclusion In conclusion, these results suggest that liraglutide should be used with caution in patients who are suffering or have the personal history of triple negative breast cancer. However, more detailed studies are required to deepen understanding of liraglutide consequences in triple negative breast cancer. ▶Graphical Abstract.

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