ATP-binding Cassette Transporter Superfamily Research Articles

Reversal Potentials of Tween 20 in ABC Transporter-Mediated Multidrug-Resistant Cancer and Treatment-Resistant Depression Through Interacting with Both Drug-Binding and ATP-Binding Areas on MDR proteins

Drug efflux transporters, especially those belonging to the ATP-binding cassette (ABC) transporter superfamily, play a crucial role in various drug resistance issues, including multidrug resistance (MDR) in cancer and treatment-resistant depression (TRD) in individuals with major depressive disorder. Key transporters in this context include P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). This study aimed to investigate the modulatory effects of polyoxyethylene (20) sorbitan monolaurate (Tween 20) on these efflux transporters in vitro and to evaluate its potential for overcoming drug resistance in two models: an in vitro cancer MDR model and an in vivo TRD model. The findings indicated that 0.001% Tween 20 significantly inhibited the efflux actions of all three transporters. Additionally, 0.005% Tween 20 effectively reversed resistance to paclitaxel, vincristine, doxorubicin, and mitoxantrone in various cancer MDR cell lines. In the in vivo depression-like behavior model, 0.01% Tween 20 markedly enhanced the antidepressant and anxiolytic effects of fluoxetine. Given its strong inhibitory effects on P-gp, MRP1, and BCRP, along with its capacity to reverse drug resistance both in vitro and in vivo, Tween 20 is a compelling candidate for tackling transporter-mediated drug resistance.

Structural insights into the mechanotransducing mechanism of FtsEX in cell division.

The filamentous temperature-sensitive (Fts) protein FtsEX plays a pivotal role in Escherichia coli (E. coli) cell division by facilitating the activation of peptidoglycan hydrolysis through the adaptor EnvC. FtsEX belongs to the type VII ATP-binding cassette (ABC) transporter superfamily, which harnesses ATP energy to induce mechanical force, triggering a cascade of conformational changes that activate the pathway. However, the precise mechanism by which FtsEX initiates mechanotransmission remains elusive. Due to the inherent instability of this type of ABC transporter protein in vitro, the conformation of FtsEX has solely been determined in the stabilized ATP-bound state. To elucidate the dynamics of FtsEX, we characterized FtsEX and EnvC of various functional structures through cryo-electron microscopy (cryo-EM) and homology modeling. We validated the structures by molecular dynamics simulations. By site-directed mutagenesis and phenotype screening, we also identified the functional residues involved in allosteric communication between FtsE and FtsX as well as FtsX and EnvC. Additionally, we discovered a potential role of phospholipids in stabilizing the complex conformation during mechanotransmission. This comprehensive exploration significantly enhances our understanding of the intricate mechanisms governing bacterial cell division and unveils potential molecular targets for developing innovative antimicrobial drugs to combat antibiotic resistance.

Genotypic spectrum of ABCA4-associated retinal degenerations in 211 unrelated Mexican patients: identification of 22 novel disease-causing variants

The purpose of this study was to analyze and molecularly describe the largest group of patients with ABCA4-associated retinal degeneration in Latin America. Pathogenic variants in ABCA4, a member of the ATP Binding Cassette (ABC) transporters superfamily, is one of the most common causes of inherited visual deficiency in humans. Retinal phenotypes associated with genetic defects in ABCA4 are collectively known as ABCA4-associated retinal degenerations (ABCA4R), a group of recessively inherited disorders associated with a high allelic heterogeneity. While large groups of Caucasian and Asiatic individuals suffering from ABCA4R have been well characterized, molecular information from certain ethnic groups is limited or unavailable, precluding a more realistic knowledge of ABCA4-related mutational profile worldwide. In this study, we describe the molecular findings of a large group of 211 ABCA4R index cases from Mexico. Genotyping was performed using either next generation sequencing (NGS) of a retinal dystrophy genes panel or exome. ABCA4 targeted mutation testing was applied to a subgroup of subjects in whom founder mutations were suspected. A total of 128 different ABCA4 pathogenic variants were identified, including 22 previously unpublished variants. The most common type of genetic variation was single nucleotide substitutions which occurred in 92.7% (408/440 alleles). According to the predicted protein effect, the most frequent variant type was missense, occurring in 83.5% of disease-causing alleles (368/440). Mutations such as p.Ala1773Val are fully demonstrated as a founder effect in native inhabitants of certain regions of Mexico. This study also gives us certain indications of other founder effects that need to be further studied in the near future. This is the largest molecularly characterized ABCA4R Latin American cohort, and our results supports the value of conducting genetic screening in underrepresented populations for a better knowledge of the mutational profile leading to monogenic diseases.

Structure and function of the Arabidopsis ABC transporter ABCB19 in brassinosteroid export.

Brassinosteroids are steroidal phytohormones that regulate plant development and physiology, including adaptation to environmental stresses. Brassinosteroids are synthesized in the cell interior but bind receptors at the cell surface, necessitating a yet to be identified export mechanism. Here, we show that a member of the ATP-binding cassette (ABC) transporter superfamily, ABCB19, functions as a brassinosteroid exporter. We present its structure in both the substrate-unbound and the brassinosteroid-bound states. Bioactive brassinosteroids are potent activators of ABCB19 ATP hydrolysis activity, and transport assays showed that ABCB19 transports brassinosteroids. In Arabidopsis thaliana, ABCB19 and its close homolog, ABCB1, positively regulate brassinosteroid responses. Our results uncover an elusive export mechanism for bioactive brassinosteroids that is tightly coordinated with brassinosteroid signaling.

Comparing ATPase activity of ATP-binding cassette subfamily C member 4, lamprey CFTR, and human CFTR using an antimony-phosphomolybdate assay.

Introduction: ATP-binding cassette (ABC) transporters use the hydrolysis of ATP to power the active transport of molecules, but paradoxically the cystic fibrosis transmembrane regulator (CFTR, ABCC7) forms an ion channel. We previously showed that ATP-binding cassette subfamily C member 4 (ABCC4) is the closest mammalian paralog to CFTR, compared to other ABC transporters. In addition, Lamprey CFTR (Lp-CFTR) is the oldest known CFTR ortholog and has unique structural and functional features compared to human CFTR (hCFTR). The availability of these evolutionarily distant orthologs gives us the opportunity to study the changes in ATPase activity that may be related to their disparate functions. Methods: We utilized the baculovirus expression system with Sf9 insect cells and made use of the highly sensitive antimony-phosphomolybdate assay for testing the ATPase activity of human ABCC4 (hABCC4), Lp-CFTR, and hCFTR under similar experimental conditions. This assay measures the production of inorganic phosphate (Pi) in the nanomolar range. Results: Crude plasma membranes were purified, and protein concentration, determined semi-quantitatively, of hABCC4, Lp-CFTR, and hCFTR ranged from 0.01 to 0.36μg/μL. No significant difference in expression level was found although hABCC4 trended toward the highest level. hABCC4 was activated by ATP with the equilibrium constant (Kd) 0.55 ± 0.28mM (n = 8). Estimated maximum ATPase rate (Vmax) for hABCC4 was about 0.2nmol/μg/min when the protein was activated with 1mM ATP at 37°C (n = 7). Estimated maximum ATPase rate for PKA-phosphorylated Lp-CFTR reached about half of hCFTR levels in the same conditions. Vmax for both Lp-CFTR and hCFTR were significantly increased in high PKA conditions compared to low PKA conditions. Maximum intrinsic ATPase rate of hABCC4 in the absence of substrate was twice that of hCFTR when activated in 1mM ATP. Conclusion: The findings here suggest that while both ABCC4 and hCFTR bear one consensus and one degenerate ATPase site, the hCFTR exhibited a reduced intrinsic ATPase activity. In addition, ATPase activity in the CFTR lineage increased from Lp-CFTR to hCFTR. Finally, the studies pave the way to purify hABCC4, Lp-CFTR, and hCFTR from Sf9 cells for their structural investigation, including by cryo-EM, and for studies of evolution in the ABC transporter superfamily.

Unravelling HetC as a peptidase-based ABC exporter driving functional cell differentiation in the cyanobacterium Nostoc PCC 7120.

The export of peptides or proteins is essential for a variety of important functions in bacteria. Among the diverse protein-translocation systems, peptidase-containing ABC transporters (PCAT) are involved in the maturation and export of quorum-sensing or antimicrobial peptides in Gram-positive bacteria and of toxins in Gram-negative organisms. In the multicellular and diazotrophic cyanobacterium Nostoc PCC 7120, the protein HetC is essential for the differentiation of functional heterocysts, which are micro-oxic and non-dividing cells specialized in atmospheric nitrogen fixation. HetC shows similarities to PCAT systems, but whether it actually acts as a peptidase-based exporter remains to be established. In this study, we show that the N-terminal part of HetC, encompassing the peptidase domain, displays a cysteine-type protease activity. The conserved catalytic residues conserved in this family of proteases are essential for the proteolytic activity of HetC and the differentiation of heterocysts. Furthermore, we show that the catalytic residue of the ATPase domain of HetC is also essential for cell differentiation. Interestingly, HetC has a cyclic nucleotide-binding domain at its N-terminus which can bind ppGpp in vitro and which is required for its function in vivo. Our results indicate that HetC is a peculiar PCAT that might be regulated by ppGpp to potentially facilitate the export of a signaling peptide essential for cell differentiation, thereby broadening the scope of PCAT role in Gram-negative bacteria.IMPORTANCEBacteria have a great capacity to adapt to various environmental and physiological conditions; it is widely accepted that their ability to produce extracellular molecules contributes greatly to their fitness. Exported molecules are used for a variety of purposes ranging from communication to adjust cellular physiology, to the production of toxins that bacteria secrete to fight for their ecological niche. They use export machineries for this purpose, the most common of which energize transport by hydrolysis of adenosine triphosphate. Here, we demonstrate that such a mechanism is involved in cell differentiation in the filamentous cyanobacterium Nostoc PCC 7120. The HetC protein belongs to the ATP-binding cassette transporter superfamily and presumably ensures the maturation of a yet unknown substrate during export. These results open interesting perspectives on cellular signaling pathways involving the export of regulatory peptides, which will broaden our knowledge of how these bacteria use two cell types to conciliate photosynthesis and nitrogen fixation.

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches.

Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer's disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.

Application Gene Variation Detection before and after Hematopoietic Stem Cell Transplantation to Predict the Relapse of Hematopoietic Neoplasm Patients after Transplantation: Retrospective Data from a Single Center in China

Objective: To evaluate the changes of gene variation in patients with hematological neoplasms at the time of diagnosis and after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and the relationship between gene mutation and recurrence after transplantation. Methods: 76 patients with hematological neoplasms were analyzed retrospectively, including 69 acute myeloid leukemia, 21 acute lymphoblastic leukemia, 5 myelodysplastic syndrome, 1 mixed acute leukemia and 1 chronic myelomonocytic leukemia. The median age was 37 (7-63) years, with 52 males and 45 females. Among 97 patients, 21 were matched sibling donor HSCT (MDS-HSCT), 14 were matched unrelated donor HSCT (MUS-HSCT), and 62 were haploidentical HSCT (haplo-HSCT). There were 88 cases of myeloablative conditioning regimen and 9 cases of non-myeloablative conditioning regimen. All patients underwent next generation sequencing (NGS) of hematological neoplasms variation genes at the time of diagnosis and 28 days after transplantation. Results: Primary and Secondary variations were detected in 89 of 97 patients during diagnosis. Common variations include CEBPA (18/97), NRAS (13/97), FLT3 (12/97), DNMT3A (11/97), TP53 (9/97), etc. After transplantation, only 29 patients had primary and Secondary variations, including ABCB1 (30/97), CYP2C19 (13/97); The number of other variations did not exceed 3 cases. The above NGS detection results suggest that the number of primary and Secondary variations after transplantation is significantly reduced (p=0.019), and ABCB1 and CYP2C19 are the main variation forms. The membrane related protein encoded by ABCB1 is a member of the ATP binding cassette (ABC) transporter superfamily, and CYP2C19 is a drug metabolizing enzyme, both of which are involved in drug metabolism. Single Nucleotide Polymorphisms (SNP) variations were detected in 52 of 97 patients at diagnosis, and GATA2 (27/97) and TET2 (25/97) variations were the most common variation forms. SNP variations of GATA2 and TET2 increased significantly after transplantation, 59/97 and 54/97 respectively. The increase of GATA2/TET2 double variation was more significant after transplantation (19/97 vs. 46/97, P<0.001). The increased variation frequency of GATA2 and TET2 after transplantation may be related to the mixed chimerism at the early stage of transplantation, which needs to be observed for a long time. Furthermore, we analyzed the relationship between gene variation and recurrence of 97 patients with hematological neoplasms at the time of diagnosis and after allo-HSCT. Eleven of 97 patients recurred after transplantation. The single factor competitive risk model showed that the presence of primary and Secondary variations after transplantation was an independent risk factor for recurrence (P=0.017) (Figure 1). The primary and secondary variations before transplantation, SNP variations before and after transplantation had no effect on recurrence after transplantation. The schemes of transplantation in 29 patients with primary and secondary variations after transplantation were analyzed, including 9 cases of MSD-HSCT, 14 cases of haplo-HSCT, and 6 cases of MUD-HSCT. It suggests that relative donors are more likely to have primary and secondary variations related to diseases. We used Fisher's Exact Test to analyze the relationship between ASXL1, TP53, GATA2, RUNX1 and other high-risk variations at the time of diagnosis/after transplantation and recurrence, and did not find that the presence of these gene variations would increase the risk of recurrence after transplantation. Conclusion: The NGS gene variation detection before and after transplantation can predict the recurrence after transplantation. Large samples and long-term monitoring are also needed to find a more accurate variation pattern to predict the recurrence of hematological neoplasms after transplantation.

Genome-wide identification and characterization of ABC transporter superfamily in the legume Cajanus cajan.

Plant ATP-binding cassette (ABC) protein family is the largest multifunctional highly conserved protein superfamily that transports diverse substrates across biological membranes by the hydrolysis of ATP and is also the part of the several other biological processes like cellular detoxification, growth and development, stress biology, and signaling processes. In the agriculturally important legume crop Cajanus cajan, a genome-wide identification and characterization of the ABC gene family was carried out. A total of 159 ABC genes were identified that belong to eight canonical classes CcABCA to CcABCG and CcABCI based on the phylogenetic analysis. The number of genes was highest in CcABCG followed by CcABCC and CcABCB class. A total of 85 CcABC genes were found on 11 chromosomes and 74 were found on scaffold. Tandem duplication was the major driver of CcABC gene family expansion. The dN/dS ratio revealed the purifying selection. The phylogenetic analysis revealed class-specific eight superclades which reflect their functional importance. The largest clade was found to be CcABCG which reflects their functional significance. CcABC proteins were mainly basic in nature and found to be localized in the plasma membrane. The secondary structure prediction revealed the dominance of α-helix. The canonical transmembrane and nucleotide binding domain, signature motif LSSGQ, Walker A, Walker B region, and Q loop were also identified. A class-specific exon-intron pattern was also observed. In addition to core elements, different cis-acting regulatory elements like stress, hormone, and cellular responsive were also identified. Expression profiling of CcABC genes at various developmental stages of different anatomical tissues was performed and it was noticed that CcABCF3, CcABCF4, CcABCF5, CcABCG66, and CcABCI3 had the highest expression. The results of the current study endow us with the further functional analysis of Cajanus ABC in the future.

Association between α-defensin 5 and the expression and function of P-glycoprotein in differentiated intestinal Caco-2 cells.

α-Defensin 5 is known to be secreted by Paneth cells in the small intestine and plays an important role in eliminating pathogenic microorganisms. It has been reported that a decrease in α-defensin 5 level in the human small intestine is a risk of inflammatory bowel disease (IBD). Furthermore, P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter superfamily, encoded by the ABCB1/MDR1 gene, plays an important role in the front line of host defense by protecting the gastrointestinal barrier from xenobiotic accumulation and may contribute to the development and persistence of IBD. Therefore, we examined the relationship between α-defensin 5 and the expression and function of P-gp using a human gastrointestinal model cell line (Caco-2). We found that MDR1 mRNA and P-gp protein level were increased in Caco-2 cells as well as α-defensin 5 secretion corresponded with the duration of cell culture. Exposure to α-defensin 5 peptide and recombinant tumor necrosis factor-α (TNF-α) significantly increased the expression and function P-gp. The mRNA levels of interleukin (IL)-8, IL-6, TNF-α, IL-1β, and IL-2 were also increased following exposure to TNF-α, similar to α-defensin 5 treatment. These results suggest that α-defensin 5 regulates P-gp expression and function by increasing TNF-α expression in Caco-2 cells.

Human ATP Binding Cassette Superfamily and Profiling Subfamily-Specific Motif for Classification

The ATP binding cassette (ABC) transporter superfamily is ubiquitous in all three domains of life. The cellular and molecular functions of ABC transporters are diverse and essential to all living organisms. In human, mutations associated with ABC transporters are known to cause many genetic diseases. Although the members of ABC transporter superfamily share common sequential feature, the subfamily recognition is not a trivial task because of its domain complexity. The functional annotation begins with subfamily recognition. Here, we showed that a motif profiling provides simple and intuitive approach to recognize the subfamily level. Along with relation to the structural feature, the motif profiling approach will be a guide to annotate and understand molecular functions of subfamilies with a big superfamily

Delayed Diagnosis of Chronic Necrotizing Granulomatous Skin Lesions due to TAP2 Deficiency.

Major histocompatibility complex class I (MHC-I) deficiency, also known as bare lymphocyte syndrome type 1 (BLS-1), is a rare autosomal recessively inherited immunodeficiency disorder with remarkable clinical and biological heterogeneity. Transporter associated with antigen processing (TAP) is a member of the ATP-binding cassette superfamily of transporters and consists of two subunits, TAP1 or TAP2. Any defect resulting from a mutation or deletion of these two subunits may adversely affect the peptide translocation in the endoplasmic reticulum, which is an important process for properly assembling MHC-I molecules. To date, only 12 TAP2-deficient patients were reported in the literature. Herein, we described two Iranian cases with 2 and 3 decades of delayed diagnosis of chronic necrotizing granulomatous skin lesions due to TAP2 deficiency without pulmonary involvement. Segregation analysis in family members identified 3 additional homozygous asymptomatic carriers. In both asymptomatic and symptomatic carriers, HLA-I expression was only 4-15% of the one observed in healthy controls. We performed the first deep immunophenotyping in TAP2-deficient patients. While total CD8 T cell counts were normal as previously reported, the patients showed strongly impaired naïve CD8 T cell counts. Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cell counts were increased.

In silico drug repurposing and lipid bilayer molecular dynamics puzzled out potential breast cancer resistance protein (BCRP/ABCG2) inhibitors

Multidrug resistance (MDR) is a fundamental reason for the fiasco of carcinoma chemotherapy. A wide variety of anticarcinoma drugs are expelled from neoplasm cells through the ATP-binding cassette (ABC) transporter superfamily, rendering the neoplasm cells resistant to treatment. The ATP-binding cassette transporter G2 (ABCG2, gene symbol BCRP) is an ABC efflux transporter that plays a key function in MDR to antineoplastic therapies. For these reasons, the identification of medicaments as BCRP inhibitors could assist in discovering better curative approaches for breast cancer therapy. Because of the deficiency of prospective BCRP inhibitors, the SuperDRUG2 database was virtually screened for inhibitor activity towards the BCRP transporter using molecular docking computations. The most potent drug candidates were then characterized utilizing molecular dynamics (MD) simulations. Furthermore, molecular mechanics-generalized Born surface area (MM-GBSA) binding affinities of the most potent drug candidates were estimated. Based on the MM-GBSA binding affinities throughout 150 ns MD simulations, three drugs—namely zotarolimus (SD002595), temsirolimus (SD003393), and glecaprevir (SD006009)—revealed greater binding affinities towards BCRP transporter compared to the co-crystallized BWQ ligand with ΔG binding values of –86.6 ± 5.6, –79.5 ± 8.0, –75.8 ± 4.6 and –59.5 ± 4.1 kcal/mol, respectively. The steadiness of these promising drugs bound with BCRP transporter was examined utilizing their structural and energetical analyses throughout a 150 ns MD simulation. To imitate the physiological environment, 150 ns MD simulations for the identified drugs bound with BCRP transporter were conducted in the 1-palmitoyl-2-oleoyl-phosphatidylcholine lipid bilayer. These findings identify zotarolimus, temsirolimus and glecaprevir as auspicious anti-MDR drug leads that warrant further experimental assays. Communicated by Ramaswamy H. Sarma

The role of bacterial ATP-binding cassette (ABC) transporters in pathogenesis and virulence: Therapeutic and vaccine potential

The ATP-binding cassette (ABC) transporter superfamily is found in all domains of life, facilitating critical biological processes through the translocation of a wide variety of substrates from, ions to proteins, across cellular membranes in an ATP-coupled process. The role of ABC transporters in eukaryotes has been well established: the facilitation of genetic diseases and multi-drug resistance (MDR) in cancer patients. In contrast, the role of ABC transporters in prokaryotes has been ambiguous due to their diverse functions and the sheer number of organisms in which they reside. This review examines the role of bacterial ABC transporters in pathogenesis and virulence, and their potential for therapeutic and vaccine application. We demonstrate how ABC transporters play a vital role in the virulence and pathogenesis of several pathogenic bacteria through the import of essential molecules, such as metal ions, amino acids, peptides, vitamins and osmoprotectants, as well as, the export of virulent determinants involved in glycoconjugate biosynthesis and Type I secretion. Furthermore, ABC exporters facilitate the persistence of pathogenic bacteria through the export of toxic xenobiotic substances, thus, contributing to the development of antimicrobial resistance. We also show that ABC transporters display considerable potential for therapeutic application through immunisation and resistance reversal. In conclusion, bacterial ABC transporters play an immense role in virulence and pathogenesis and display desirable traits for clinical use, therefore, potentially aiding in the battle against MDR.

Deciphering the roles of ABCB5 in normal and cancer cells

ABCB5 encodes a full transporter (ABCB5FL) and a half transporter (ABCB5β), which is unique in the ATP binding cassette (ABC) transporter superfamily. We discuss the roles of both isoforms in undifferentiated slow-cycling cells, multidrug resistance, and tumorigenesis, and their regulation pathways.

Association between G2677T/A polymorphism in ABCB1 gene and the risk of drug resistance epilepsy: An updated systematic review and meta-analysis

PurposeEpilepsy is a common serious brain condition characterized by the abnormal electrical activity of neurons. In most cases, epileptic patients respond to antiepileptic drugs. Approximately, one-third of patients prove medically intractable. The ABCB1 gene is a superfamily of ATP-binding cassette (ABC) transporters that encode a drug-transport protein, lead to cells and organs protects and eliminates toxic agents. We performed this meta-analysis to assess the association between G2677T/A in the ABCB1 gene and the risk of drug resistance in epileptic patients. MethodsTwo online libraries (PubMed and Scopus) were used to identify studies that report the relationship between G2677T/A polymorphism in the MDR1 gene and the risk of antiepileptic drug resistance. The meta-analysis was performed using Review Manager 5.3 software. The pooled odds ratios and 95 % confidence intervals (CIs) were calculated using a random or fixed effects model according to the heterogeneity between studies. ResultsA total of 33 eligible studies were included in this meta-analysis which 4192 patients were drug-resistant and 5079 patients were drug-responsive. As a result, a significant association was observed in overall population for the genetic model GG+GA vs AA (OR with 95 % CI = 0,56 [0.34,0.93]; P = 0.02). The subgroup ethnicity analysis showed a significant decrease in the risk of AEDs resistance in the Caucasian population. ConclusionIn conclusion, our analysis demonstrates that G2677T/A polymorphism in the ABCB1 gene decreases the risk of drug resistance. More studies are needed in the different ethnic groups to clarify the role of polymorphism in AEDs resistance.

Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration.

ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) transporters that is preferentially localized along the rim region of rod and cone photoreceptor outer segment disc membranes. It uses the energy from ATP binding and hydrolysis to transport N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff base adduct of retinal and phosphatidylethanolamine, from the lumen to the cytoplasmic leaflet of disc membranes. This ensures that all-trans-retinal and excess 11-cis-retinal are efficiently cleared from photoreceptor cells thereby preventing the accumulation of toxic retinoid compounds. Loss-of-function mutations in the gene encoding ABCA4 cause autosomal recessive Stargardt macular degeneration, also known as Stargardt disease (STGD1), and related autosomal recessive retinopathies characterized by impaired central vision and an accumulation of lipofuscin and bis-retinoid compounds. High resolution structures of ABCA4 in its substrate and nucleotide free state and containing bound N-Ret-PE or ATP have been determined by cryo-electron microscopy providing insight into the molecular architecture of ABCA4 and mechanisms underlying substrate recognition and conformational changes induced by ATP binding. The expression and functional characterization of a large number of disease-causing missense ABCA4 variants have been determined. These studies have shed light into the molecular mechanisms underlying Stargardt disease and a classification that reliably predicts the effect of a specific missense mutation on the severity of the disease. They also provide a framework for developing rational therapeutic treatments for ABCA4-associated diseases.

The human ATP-binding cassette (ABC) transporter superfamily.

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intracellular 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. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases. We analyzed ABC gene conservation within human populations and across vertebrates and surveyed phenotypes of ABC gene mutations in mice. Most mouse ABC gene disruption mutations have a phenotype that mimics human disease, indicating they are applicable models. Interestingly, several ABCA family genes, whose human function is unknown, have cholesterol level phenotypes in the mouse. Genome-wide association studies confirm and extend ABC traits and suggest several new functions to investigate. Whole-exome sequencing of tumors from diverse cancer types demonstrates that mutations in ABC genes are not common in cancer, but specific genes are overexpressed in select tumor types. Finally, an analysis of the frequency of loss-of-function mutations demonstrates that many human ABC genes are essential with a low level of variants, while others have a higher level of genetic diversity.

Exploring the transportome of the biosurfactant producing yeast Starmerella bombicola

Starmerella bombicola is a non-conventional yeast mainly known for its capacity to produce high amounts of the glycolipids ‘sophorolipids’. Although its product has been used as biological detergent for a couple of decades, the genetics of S. bombicola are still largely unknown. Computational analysis of the yeast’s genome enabled us to identify 254 putative transporter genes that make up the entire transportome. For each of them, a potential substrate was predicted using homology analysis, subcellular localization prediction and RNA sequencing in different stages of growth. One transporter family is of exceptional importance to this yeast: the ATP Binding Cassette (ABC) transporter Superfamily, because it harbors the main driver behind the highly efficient sophorolipid export. Furthermore, members of this superfamily translocate a variety of compounds ranging from antibiotics to hydrophobic molecules. We conducted an analysis of this family by creating deletion mutants to understand their role in the export of hydrophobic compounds, antibiotics and sophorolipids. Doing this, we could experimentally confirm the transporters participating in the efflux of medium chain fatty alcohols, particularly decanol and undecanol, and identify a second sophorolipid transporter that is located outside the sophorolipid biosynthetic gene cluster.

The molecular evolution of function in the CFTR chloride channel.

The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand-channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.