Статті в журналах: "Major Facilitator Super family"

1

Motoi, Yuji, Mayumi Saeki, Tomoe Nishimura, Kazufumi Katayama, Noriko Kitamura, Hitoshi Ichikawa, Hiroyuki Miyoshi, Osamu Kaminuma, and Takachika Hiroi. "Establishment of monoclonal antibodies against a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10." Immunology Letters 147, no. 1-2 (September 2012): 80–84. http://dx.doi.org/10.1016/j.imlet.2012.07.001.

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Nishimura, Tomoe, Mayumi Saeki, Yuji Motoi, Noriko Kitamura, Akio Mori, Osamu Kaminuma, and Takachika Hiroi. "Selective Suppression of Th2 Cell-Mediated Lung Eosinophilic Inflammation by Anti-Major Facilitator Super Family Domain Containing 10 Monoclonal Antibody." Allergology International 63 (2014): 29–35. http://dx.doi.org/10.2332/allergolint.13-oa-0635.

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Ceasar, S. Antony, Alison Baker, Stephen P. Muench, S. Ignacimuthu, and Stephen A. Baldwin. "The conservation of phosphate-binding residues among PHT1 transporters suggests that distinct transport affinities are unlikely to result from differences in the phosphate-binding site." Biochemical Society Transactions 44, no. 5 (October 15, 2016): 1541–48. http://dx.doi.org/10.1042/bst20160016.

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The plant PHosphate Transporter 1 (PHT1) family of membrane proteins belongs to the major facilitator super family and plays a major role in the acquisition of inorganic phosphate (Pi) from the soil and its transport within the plant. These transporters have been well characterized for expression patterns, localization, and in some cases affinity. Furthermore, the crystal structure of a high-affinity eukaryotic phosphate transporter from the fungus Piriformospora indica (PiPT) has revealed important information on the residues involved in Pi transport. Using multiple-sequence alignments and homology modelling, the phosphate-binding site residues were shown to be well conserved between all the plant PHT1 proteins, Saccharomyces cerevisiae PHO84 and PiPT. For example, Asp 324 in PiPT is conserved in the equivalent position in all plant PHT1 and yeast transporters analyzed, and this residue in ScPHO84 was shown by mutagenesis to be important for both the binding and transport of Pi. Moreover, Asp 45 and Asp 149, which are predicted to be involved in proton import, and Lys 459, which is putatively involved in Pi-binding, are all fully conserved in PHT1 and ScPHO84 transporters. The conserved nature of the residues that play a key role in Pi-binding and transport across the PHT1 family suggests that the differing Pi affinities of these transporters do not reside in differences in the Pi-binding site. Recent studies suggest that phosphate transporters could possess dual affinity and that post-translational modifications may be important in regulating affinity for phosphate.

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D'Cruz, Louise M., Ann Piccirillo, Eric Hyzny, Ashley Menk, Callen Wallace, William F. Hawse, Heather Marie Buechel, et al. "The lysophosphatidylcholine transporter, MFSD2A, is essential for CD8+ memory T cell maintenance and secondary response to infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 122.3. http://dx.doi.org/10.4049/jimmunol.202.supp.122.3.

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Abstract Access to nutrients is critical for an effective T cell immune response to infection. Although transporters for sugars and amino acids have previously been described in the context of the CD8+ T cell immune response, the active transport of exogenous fatty acids has remained enigmatic. Here we discovered the sodium-dependent lysophosphatidylcholine transporter, Major Facilitator Super Family Domain Containing 2a (MFSD2A), is upregulated on activated CD8+ T cells and is required for memory T cell maintenance. MFSD2A deficiency in mice resulted in decreased import of lysophosphatidylcholine (LPC) esterified to long chain fatty acids (LCFAs) into activated CD8+ T cells, and MFSD2A deficient cells are at a competitive disadvantage resulting in reduced memory T cell formation and maintenance and reduced response to secondary infection. Mechanistically, import of LPCs was required to maintain T cell homeostatic turnover, that when lost resulted in a decreased memory T cell pool and thus a reduced secondary response to repeat infection.

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Piccirillo, Ann R., William F. Hawse, Heather M. Buechel, David L. Silver, and Louise M. D’Cruz. "The long chain fatty acid transporter, MFSD2A, is essential for memory CD8+ T cell formation and maintenance." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 51.3. http://dx.doi.org/10.4049/jimmunol.200.supp.51.3.

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Abstract Access to nutrients is critical for an effective T cell immune response to infection. Although transporters for sugars and amino acids have previously been described in the context of the CD8+ T cell immune response, the active transport of exogenous esterified fatty acids has remained enigmatic. Here we discovered the long chain fatty acid transporter, Major Facilitator Super Family Domain Containing 2a (MFSD2A), is upregulated on activated CD8+ T cells and is essential for their memory cell formation. MFSD2A deficiency resulted in decreased import of long chain fatty acids (LCFAs) esterified to lysophosphatidylcholine (LPC) into activated CD8+ T cells but overall resulted in a normal primary effector T cell response. However, loss of MFSD2A led to reduced memory T cell formation and maintenance. MFSD2A deficient memory CD8+ T cells showed reduced CD127 and CD62L expression and their cell turnover was significantly impaired in contrast to their wildtype counterparts. Moreover, the secondary response to infection was severely diminished in MFSD2A deficient T cells. Mechanistically, import of LCFAs was required to maintain cell energy requirements and ‘fitness’, that when lost resulted in a decreased memory T cell pool and inability to proliferate upon secondary stimulation. Our results show that MFSD2A and LPC may be useful for future small molecule therapy design to generate a more robust T cell response for new vaccines or cancer treatments.

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Pao, Stephanie S., Ian T. Paulsen, and Milton H. Saier. "Major Facilitator Superfamily." Microbiology and Molecular Biology Reviews 62, no. 1 (March 1, 1998): 1–34. http://dx.doi.org/10.1128/mmbr.62.1.1-34.1998.

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SUMMARY The major facilitator superfamily (MFS) is one of the two largest families of membrane transporters found on Earth. It is present ubiquitously in bacteria, archaea, and eukarya and includes members that can function by solute uniport, solute/cation symport, solute/cation antiport and/or solute/solute antiport with inwardly and/or outwardly directed polarity. All homologous MFS protein sequences in the public databases as of January 1997 were identified on the basis of sequence similarity and shown to be homologous. Phylogenetic analyses revealed the occurrence of 17 distinct families within the MFS, each of which generally transports a single class of compounds. Compounds transported by MFS permeases include simple sugars, oligosaccharides, inositols, drugs, amino acids, nucleosides, organophosphate esters, Krebs cycle metabolites, and a large variety of organic and inorganic anions and cations. Protein members of some MFS families are found exclusively in bacteria or in eukaryotes, but others are found in bacteria, archaea, and eukaryotes. All permeases of the MFS possess either 12 or 14 putative or established transmembrane α-helical spanners, and evidence is presented substantiating the proposal that an internal tandem gene duplication event gave rise to a primordial MFS protein prior to divergence of the family members. All 17 families are shown to exhibit the common feature of a well-conserved motif present between transmembrane spanners 2 and 3. The analyses reported serve to characterize one of the largest and most diverse families of transport proteins found in living organisms.

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Grover, Amit, and Rakesh Sharma. "Identification and Characterization of a Major Zn(II) Resistance Determinant of Mycobacterium smegmatis." Journal of Bacteriology 188, no. 19 (October 1, 2006): 7026–32. http://dx.doi.org/10.1128/jb.00643-06.

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ABSTRACT A zinc ion-sensitive mutant of Mycobacterium smegmatis was isolated. The transposon insertion was located in zitA (MSMEG0750), a gene coding for a cation diffusion facilitator family protein. Zinc ions specifically induced expression of zitA. In silico analysis revealed that environmental and opportunistic pathogenic species contain higher numbers of cation diffusion facilitator genes than do obligate pathogens.

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Kumar, Sanath, Manjusha Lekshmi, Ammini Parvathi, Manisha Ojha, Nicholas Wenzel, and Manuel F. Varela. "Functional and Structural Roles of the Major Facilitator Superfamily Bacterial Multidrug Efflux Pumps." Microorganisms 8, no. 2 (February 16, 2020): 266. http://dx.doi.org/10.3390/microorganisms8020266.

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Pathogenic microorganisms that are multidrug-resistant can pose severe clinical and public health concerns. In particular, bacterial multidrug efflux transporters of the major facilitator superfamily constitute a notable group of drug resistance mechanisms primarily because multidrug-resistant pathogens can become refractory to antimicrobial agents, thus resulting in potentially untreatable bacterial infections. The major facilitator superfamily is composed of thousands of solute transporters that are related in terms of their phylogenetic relationships, primary amino acid sequences, two- and three-dimensional structures, modes of energization (passive and secondary active), and in their mechanisms of solute and ion translocation across the membrane. The major facilitator superfamily is also composed of numerous families and sub-families of homologous transporters that are conserved across all living taxa, from bacteria to humans. Members of this superfamily share several classes of highly conserved amino acid sequence motifs that play essential mechanistic roles during transport. The structural and functional importance of multidrug efflux pumps that belong to the major facilitator family and that are harbored by Gram-negative and -positive bacterial pathogens are considered here.

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Pratiwi, Indah D. "Family presence during resuscitation: patient and family members’ preferences and attitudes." International Journal of Research in Medical Sciences 6, no. 2 (January 24, 2018): 394. http://dx.doi.org/10.18203/2320-6012.ijrms20180275.

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Background: This literature review presents a review of the available studies into family presence during resuscitation (FPDR) in the context of emergency department and critical care unit from the point of view of patients and family members. This literature review provides the background for understanding the debate about FPDR. The paper examines the state of current research on the topic and points out gaps in existing literature.Methods: A comprehensive search of OVID Nursing, Web of Science (Web of Knowledge), Elsevier, ProQuest and Google Scholar electronic search engine. Thematic analysis was used to extract themes from the 25 studies reviewed (quantitative, qualitative and mixed-methods studies), resulted in five major themes and five minor themes.Results: Five major themes from this literature review were: (1) patient and family members’ preferences; (2) perceived benefits of family presence during resuscitation; (3) perceiving family presence as a right; (4) the importance of a family facilitator; and (5) the involvement of decision making.Conclusions: This literature review has established the potentials of family presence during resuscitation to improve patient and family-centred care by helping and providing family members to manage and to adjust during traumatic circumstances.

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Sherwood, Peter W., Iskra Katic, Pascual Sanz, and Marian Carlson. "A Glucose Transporter Chimera Confers a Dominant Negative Glucose Starvation Phenotype in Saccharomyces cerevisiae." Genetics 155, no. 2 (June 1, 2000): 989–92. http://dx.doi.org/10.1093/genetics/155.2.989.

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Abstract A family of glucose transporters mediates glucose uptake in Saccharomyces cerevisiae. We show that the dominant mutation GSF4-1, which impairs glucose repression of SUC2, results in a nonfunctional chimera of the transporters Hxt1p and Hxt4p. Hxt1/4p inhibits the function of wild-type glucose transporters. Similar mutations may facilitate analysis of the major facilitator superfamily.

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Sigal, Nadejda, Shahar Molshanski-Mor, and Eitan Bibi. "No Single Irreplaceable Acidic Residues in the Escherichia coli Secondary Multidrug Transporter MdfA." Journal of Bacteriology 188, no. 15 (August 1, 2006): 5635–39. http://dx.doi.org/10.1128/jb.00422-06.

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ABSTRACT The largest family of solute transporters (major facilitator superfamily [MFS]) includes proton-motive-force-driven secondary transporters. Several characterized MFS transporters utilize essential acidic residues that play a critical role in the energy-coupling mechanism during transport. Surprisingly, we show here that no single acidic residue plays an irreplaceable role in the Escherichia coli secondary multidrug transporter MdfA.

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Sauve, Stephanie, Joseph Williamson, Adithya Polasa, and Mahmoud Moradi. "Ins and Outs of Rocker Switch Mechanism in Major Facilitator Superfamily of Transporters." Membranes 13, no. 5 (April 25, 2023): 462. http://dx.doi.org/10.3390/membranes13050462.

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The major facilitator superfamily (MFS) of transporters consists of three classes of membrane transporters: symporters, uniporters, and antiporters. Despite such diverse functions, MFS transporters are believed to undergo similar conformational changes within their distinct transport cycles, known as the rocker-switch mechanism. While the similarities between conformational changes are noteworthy, the differences are also important since they could potentially explain the distinct functions of symporters, uniporters, and antiporters of the MFS superfamily. We reviewed a variety of experimental and computational structural data on a select number of antiporters, symporters, and uniporters from the MFS family to compare the similarities and differences of the conformational dynamics of three different classes of transporters.

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Hirai, Teruhisa, Jürgen A. W. Heymann, Peter C. Maloney, and Sriram Subramaniam. "Structural Model for 12-Helix Transporters Belonging to the Major Facilitator Superfamily." Journal of Bacteriology 185, no. 5 (March 1, 2003): 1712–18. http://dx.doi.org/10.1128/jb.185.5.1712-1718.2003.

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ABSTRACT The major facilitator superfamily includes a large collection of evolutionarily related proteins that have been implicated in the transport of a variety of solutes and metabolites across the membranes of organisms ranging from bacteria to humans. We have recently reported the three-dimensional structure, at 6.5 Å resolution, of the oxalate transporter, OxlT, a representative member of this superfamily. In the oxalate-bound state, 12 helices surround a central cavity to form a remarkably symmetrical structure that displays a well-defined pseudo twofold axis perpendicular to the plane of the membrane as well as two less pronounced, mutually perpendicular pseudo twofold axes in the plane of the membrane. Here, we combined this structural information with sequence information from other members of this protein family to arrive at models for the arrangement of helices in this superfamily of transport proteins. Our analysis narrows down the number of helix arrangements from about a billion starting possibilities to a single probable model for the relative spatial arrangement for the 12 helices, consistent both with our structural findings and with the majority of previous biochemical studies on members of this superfamily.

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Lee, Sophie, Hilary Moss, and Desmond O’Neill. "Toward a Greater Contextualization of Music and the Arts in Aging and Cognitive Disorders." Innovation in Aging 4, Supplement_1 (December 1, 2020): 841. http://dx.doi.org/10.1093/geroni/igaa057.3084.

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Abstract Research suggests that group music-making can improve well-being and cognitive function in people with dementia and their family carers. The importance of the music facilitator’s role is recognised. However, empirical studies rarely capture their experiences and perspectives. Semi-structured interviews were conducted with three music therapists and three community musicians with specialisms in dementia care. The interviews sought to gain a detailed understanding of their work with people with dementia. Interpretative Phenomenological Analysis revealed eight super-ordinate themes: (1) benefits of music-making for people with dementia; (2) challenges of working with people with dementia; (3) involving family carers; (4) musical content; (5) impact of the facilitator; (6) developing field of Arts and Health; (7) work as a privilege; and (8) potential for misuse of music. This study provides a useful basis from which to further develop concepts for the amelioration of people living with dementia and their families.

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Quirion, R., J. G. Chabot Chabot, and Y. Dumont. "Multiple Receptor Subtypes for the CGRP Super-Family." Scientific World JOURNAL 1 (2001): 15. http://dx.doi.org/10.1100/tsw.2001.436.

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Molecular evidence for the existence of multiple receptors for CGRP has been rather difficult to obtain. Over 10 years after suggesting the existence of at least two classes (CGRP1 and CGRP2) of CGRP receptors on the basis of pharmacological data[1], molecular data on the CGRP2 receptor subtype are still lacking as well as potent and selective antagonists. The situation is somewhat different for the functional CGRP1 subtype which is likely composed of diverse subunits CRLR, RAMP1 and possibly RCP[2]. Moreover, BIBN 4096BS was recently reported as the first nonpeptide highly potent CGRP1 receptor antagonist[3]. However, in situ hybridization and receptor autoradiographic data have clearly shown the existence of major mismatches (e.g., cerebellum) between the discrete localization of CRLR, RAMP1, and specific CGRP binding sites supporting the existence of CGRP receptor subtypes. Functional studies have also provided evidence in that regard (for a recent review: [4]). Accordingly, additional studies aiming at cloning additional CGRP receptors are certainly warranted. Similarly, recent evidence from various laboratories including ours suggests the existence of more than one class (CRLR and RAMP2) of adrenomedullin receptors at least in the rat brain. In contrast, most evidence suggests the existence of a single class of amylin receptors. In brief, it appears that multiple receptors or receptor complexes do exist for CGRP and related peptides but their composition is apparently unique among the GPCR super-family and additional data are needed to fully establish the molecular organization of each subtype. Supported by CIHR of Canada.

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Ditty, Jayna L., and Caroline S. Harwood. "Charged Amino Acids Conserved in the Aromatic Acid/H+ Symporter Family of Permeases Are Required for 4-Hydroxybenzoate Transport by PcaK from Pseudomonas putida." Journal of Bacteriology 184, no. 5 (March 1, 2002): 1444–48. http://dx.doi.org/10.1128/jb.184.5.1444-1448.2002.

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ABSTRACT Charged amino acids in the predicted transmembrane portion of PcaK, a permease from Pseudomonas putida that transports 4-hydroxybenzoate (4-HBA), were required for 4-HBA transport, and they were also required for P. putida to have a chemotactic response to 4-HBA. An essential amino acid motif (DGXD) containing aspartate residues is located in the first transmembrane segment of PcaK and is conserved in the aromatic acid/H+ symporter family of the major facilitator superfamily of transporters.

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Titgemeyer, Fritz, Johannes Amon, Stephan Parche, Maysa Mahfoud, Johannes Bail, Maximilian Schlicht, Nadine Rehm, et al. "A Genomic View of Sugar Transport in Mycobacterium smegmatis and Mycobacterium tuberculosis." Journal of Bacteriology 189, no. 16 (June 8, 2007): 5903–15. http://dx.doi.org/10.1128/jb.00257-07.

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ABSTRACT We present a comprehensive analysis of carbohydrate uptake systems of the soil bacterium Mycobacterium smegmatis and the human pathogen Mycobacterium tuberculosis. Our results show that M. smegmatis has 28 putative carbohydrate transporters. The majority of sugar transport systems (19/28) in M. smegmatis belong to the ATP-binding cassette (ABC) transporter family. In contrast to previous reports, we identified genes encoding all components of the phosphotransferase system (PTS), including permeases for fructose, glucose, and dihydroxyacetone, in M. smegmatis. It is anticipated that the PTS of M. smegmatis plays an important role in the global control of carbon metabolism similar to those of other bacteria. M. smegmatis further possesses one putative glycerol facilitator of the major intrinsic protein family, four sugar permeases of the major facilitator superfamily, one of which was assigned as a glucose transporter, and one galactose permease of the sodium solute superfamily. Our predictions were validated by gene expression, growth, and sugar transport analyses. Strikingly, we detected only five sugar permeases in the slow-growing species M. tuberculosis, two of which occur in M. smegmatis. Genes for a PTS are missing in M. tuberculosis. Our analysis thus brings the diversity of carbohydrate uptake systems of fast- and a slow-growing mycobacteria to light, which reflects the lifestyles of M. smegmatis and M. tuberculosis in their natural habitats, the soil and the human body, respectively.

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Xie, Hao, Simon G. Patching, Maurice P. Gallagher, Gary J. Litherland, Adrian R. Brough, Henrietta Venter, Sylvia Y. M. Yao, et al. "Purification and properties of theEscherichia colinucleoside transporter NupG, a paradigm for a major facilitator transporter sub-family." Molecular Membrane Biology 21, no. 5 (January 2004): 323–36. http://dx.doi.org/10.1080/09687860400003941.

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19

Shah, Abdul Haseeb, Ashutosh Singh, Sanjiveeni Dhamgaye, Neeraj Chauhan, Patrick Vandeputte, Korivi Jyothiraj Suneetha, Rupinder Kaur, et al. "Novel role of a family of major facilitator transporters in biofilm development and virulence of Candida albicans." Biochemical Journal 460, no. 2 (May 13, 2014): 223–35. http://dx.doi.org/10.1042/bj20140010.

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QDR proteins of C. albicans do not carry out their conserved transport function, rather they affect the pathogenesis of the organism and their deletion mutants also show architectural defects in biofilms and massive remodelling of lipids as a compensatory mechanism to sustain their loss.

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Bertram, Ralph, Maximilian Schlicht, Kerstin Mahr, Harald Nothaft, Milton H. Saier, and Fritz Titgemeyer. "In Silico and Transcriptional Analysis of Carbohydrate Uptake Systems of Streptomyces coelicolor A3(2)." Journal of Bacteriology 186, no. 5 (March 1, 2004): 1362–73. http://dx.doi.org/10.1128/jb.186.5.1362-1373.2004.

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ABSTRACT Streptomyces coelicolor is the prototype for the investigation of antibiotic-producing and differentiating actinomycetes. As soil bacteria, streptomycetes can metabolize a wide variety of carbon sources and are hence vested with various specific permeases. Their activity and regulation substantially determine the nutritional state of the cell and, therefore, influence morphogenesis and antibiotic production. We have surveyed the genome of S. coelicolor A3(2) to provide a thorough description of the carbohydrate uptake systems. Among 81 ATP-binding cassette (ABC) permeases that are present in the genome, we found 45 to encode a putative solute binding protein, an essential feature for carbohydrate permease function. Similarity analysis allowed the prediction of putative ABC systems for transport of cellobiose and cellotriose, α-glucosides, lactose, maltose, maltodextrins, ribose, sugar alcohols, xylose, and β-xylosides. A novel putative bifunctional protein composed of a substrate binding and a membrane-spanning moiety is likely to account for ribose or ribonucleoside uptake. Glucose may be incorporated by a proton-driven symporter of the major facilitator superfamily while a putative sodium-dependent permease of the solute-sodium symporter family may mediate uptake of galactose and a facilitator protein of the major intrinsic protein family may internalize glycerol. Of the predicted gene clusters, reverse transcriptase PCRs showed active gene expression in 8 of 11 systems. Together with the previously surveyed permeases of the phosphotransferase system that accounts for the uptake of fructose and N-acetylglucosamine, the genome of S. coelicolor encodes at least 53 potential carbohydrate uptake systems.

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Ramchuran, Estelle J., Isabel Pérez-Guillén, Linda A. Bester, René Khan, Fernando Albericio, Miguel Viñas, and Beatriz G. de la Torre. "Super-Cationic Peptide Dendrimers—Synthesis and Evaluation as Antimicrobial Agents." Antibiotics 10, no. 6 (June 10, 2021): 695. http://dx.doi.org/10.3390/antibiotics10060695.

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Microbial infections are a major public health concern. Antimicrobial peptides (AMPs) have been demonstrated to be a plausible alternative to the current arsenal of drugs that has become inefficient due to multidrug resistance. Herein we describe a new AMP family, namely the super-cationic peptide dendrimers (SCPDs). Although all members of the series exert some antibacterial activity, we propose that special attention should be given to (KLK)2KLLKLL-NH2 (G1KLK-L2KL2), which shows selectivity for Gram-negative bacteria and virtually no cytotoxicity in HepG2 and HEK293. These results reinforce the validity of the SCPD family as a valuable class of AMP and support G1KLK-L2KL2 as a strong lead candidate for the future development of an antibacterial agent against Gram-negative bacteria.

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Sulavik, Mark C., Chad Houseweart, Christina Cramer, Nilofer Jiwani, Nicholas Murgolo, Jonathan Greene, Beth DiDomenico, et al. "Antibiotic Susceptibility Profiles ofEscherichia coli Strains Lacking Multidrug Efflux Pump Genes." Antimicrobial Agents and Chemotherapy 45, no. 4 (April 1, 2001): 1126–36. http://dx.doi.org/10.1128/aac.45.4.1126-1136.2001.

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ABSTRACT The contribution of seven known and nine predicted genes or operons associated with multidrug resistance to the susceptibility of Escherichia coli W3110 was assessed for 20 different classes of antimicrobial compounds that include antibiotics, antiseptics, detergents, and dyes. Strains were constructed with deletions for genes in the major facilitator superfamily, the resistance nodulation-cell division family, the small multidrug resistance family, the ATP-binding cassette family, and outer membrane factors. The agar dilution MICs of 35 compounds were determined for strains with deletions for multidrug resistance (MDR) pumps. Deletions in acrAB or tolC resulted in increased susceptibilities to the majority of compounds tested. The remaining MDR pump gene deletions resulted in increased susceptibilities to far fewer compounds. The results identify which MDR pumps contribute to intrinsic resistance under the conditions tested and supply practical information useful for designing sensitive assay strains for cell-based screening of antibacterial compounds.

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Jain, Shashank, Susan Russell, and Jerry Ware. "Platelet Glycoprotein VI Contributes to Murine Experimental Metastasis." Blood 112, no. 11 (November 16, 2008): 2862. http://dx.doi.org/10.1182/blood.v112.11.2862.2862.

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Abstract A key receptor supporting the normal role of platelets in hemostasis and thrombosis is the collagen receptor, glycoprotein (GP)VI. GPVI is a member of the immunoglobulin super family and is uniquely expressed on the surface of platelets where it is assembled with the ITAM-bearing activation subunit, FcR-g. We have previously reported the generation of a murine model of GP VI deficiency that revealed profound defects in collagen-induced platelet aggregation and major defects in platelet activation following adhesion under flow to fibrillar collagen. More recently, we have generated congenic GPVI deficient animals through an extensive breeding scheme to the inbred C57BL/6J strain. The relevance of specific platelet receptors in experimental metastasis is emerging with work from our laboratory establishing a key role for the platelet glycoprotein Ib- IX complex. We have now performed similar studies using congenic GPVI deficient animals. In this experimental model, murine tumor cells are placed in the tail vein of mice and establishment of lung tumor burden or lung tumor foci is examined two weeks following injection. This model represents a syngeneic model where animals are fully immunocompetent and the injected tumor cells were originally derived from animals of the C57BL/6J strain. Experiments comparing B16F10.1 cells (murine melanoma) and D121 cells (murine Lewis lung carcinoma) have been performed revealing a consistent and statistically significant reduction in tumor foci as a consequence of GPVI absence. In the case of melanoma cell injections into wild type C57BL/6J mice, a mean of 270 foci (SEM 44.0, n=6) is reduced to a mean of 134 foci (SEM 11.6, n=7) in the absence of platelet GPVI (p = 0.013). Similar reductions were observed using Lewis lung carcinoma cells with wild type animals revealing a mean of 132 surface foci (SEM 13.4, n=15) and GPVI deficient animals having a mean of 69 foci (SEM 7.9, n=12; p = 0.0003). Using either cell line an approximate reduction of 50% in the number of visible tumor foci was observed. Additional studies have been performed to compare the size and growth rate of subcutaneously implanted tumor cells, i.e., primary tumor growth. Here, we observed no noticeable size difference in primary tumors harvested 17 days following subcutaneous injection of D121 cells comparing the presence or absence of platelet GPVI. These results demonstrate in the platelet GPVI facilitates experimental tumor metastasis but does not contribute in the growth of primary tumors. These studies underscore the well-established paradigm of platelet adhesion and activation in hemostasis and thrombosis being applicable to mechanisms participating in the spread of cancer. The importance of metastasis in the prognosis for recovery from cancer can not be under emphasized. Indeed, the spread of metastatic disease represents a fundamental change in significantly shortening the life span of the cancer patient. Thus, understanding the molecules that regulate metastasis identifies potential targets for therapeutic intervention that could significantly improve the patient’s prognosis.

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Chen, Sushu, Hui Wang, David S. Katzianer, Zengtao Zhong, and Jun Zhu. "LysR family activator-regulated major facilitator superfamily transporters are involved in Vibrio cholerae antimicrobial compound resistance and intestinal colonisation." International Journal of Antimicrobial Agents 41, no. 2 (February 2013): 188–92. http://dx.doi.org/10.1016/j.ijantimicag.2012.10.008.

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Wei, Junhong, Yuqing Tian, Guoqing Niu, and Huarong Tan. "GouR, a TetR Family Transcriptional Regulator, Coordinates the Biosynthesis and Export of Gougerotin in Streptomyces graminearus." Applied and Environmental Microbiology 80, no. 2 (November 15, 2013): 714–22. http://dx.doi.org/10.1128/aem.03003-13.

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ABSTRACTGougerotin is a peptidyl nucleoside antibiotic. It functions as a specific inhibitor of protein synthesis by binding ribosomal peptidyl transferase and exhibits a broad spectrum of biological activities.gouR, situated in the gougerotin biosynthetic gene cluster, encodes a TetR family transcriptional regulatory protein. Gene disruption and genetic complementation revealed thatgouRplays an important role in the biosynthesis of gougerotin. Transcriptional analysis suggested that GouR represses the transcription of thegouL-to-gouBoperon consisting of 11 structural genes and activates the transcription of the major facilitator superfamily (MFS) transporter gene (gouM). Electrophoresis mobility shift assays (EMSAs) and DNase I footprinting experiments showed that GouR has specific DNA-binding activity for the promoter regions ofgouL,gouM, andgouR. Our data suggested that GouR modulates gougerotin production by coordinating its biosynthesis and export inStreptomyces graminearus.

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Prakash, Hariprasath, Ponmurugan Karuppiah, Naif A Al-Dhabi, Gandham S. Prasad, Chandan Badapanda, Arunaloke Chakrabarti, and Shivaprakash M. Rudramurthy. "Comparative genomics of Sporothrix species and identification of putative pathogenic-gene determinants." Future Microbiology 15, no. 15 (October 2020): 1465–81. http://dx.doi.org/10.2217/fmb-2019-0302.

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Aim: To understand the phylogenomics, pathogenic/virulence-associated genes and genomic evolution of pathogenic Sporothrix species. Materials & methods: We performed in silico comparative genome analysis of Sporothrix species using ab initio tools and in-house scripts. We predicted genes and repeats, compared genomes based on synteny, identified orthologous clusters, assessed genes family expansion/contraction, predicted secretory proteins and finally searched for similar sequences from various databases. Results: The phylogenomics revealed that Sporothrix species are closely related to Ophiostoma species. The gene family evolutionary analysis revealed the expansion of genes related to virulence (CFEM domain, iron acquisition genes, lysin motif domain), stress response (Su[var]3-9, Enhancer-of-zeste and Trithorax domain and Domain of unknown function 1996), proteases (aspartic protease, x-pro dipeptidyl-peptidase), cell wall composition associated genes (chitin deacetylase, chitinase) and transporters (major facilitator superfamily transporter, oligo-peptide transporter family) in Sporothrix species. Conclusion: The present study documents the putative pathogenic/virulence-associated genes in the Sporothrix species.

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Braibant, Martine, Jacqueline Chevalier, Elisabeth Chaslus-Dancla, Jean-Marie Pagès, and Axel Cloeckaert. "Structural and Functional Study of the Phenicol-Specific Efflux Pump FloR Belonging to the Major Facilitator Superfamily." Antimicrobial Agents and Chemotherapy 49, no. 7 (July 2005): 2965–71. http://dx.doi.org/10.1128/aac.49.7.2965-2971.2005.

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ABSTRACT The florfenicol-chloramphenicol resistance gene floR from Salmonella enterica was previously identified and postulated to belong to the major facilitator (MF) superfamily of drug exporters. Here, we confirmed a computer-predicted transmembrane topological model of FloR, using the phoA gene fusion method, and classified this protein in the DHA12 family (containing 12 transmembrane domains) of MF efflux transporters. We also showed that FloR is a transporter specific for structurally associated phenicol drugs (chloramphenicol, florfenicol, thiamphenicol) which utilizes the proton motive force to energize an active efflux mechanism. By site-directed mutagenesis of specific charged residues belonging to putative transmembrane segments (TMS), two residues essential for active efflux function, D23 in TMS1 and R109 in TMS4, were identified. Of these, the acidic residue D23 seems to participate directly in the affinity pocket involved in phenicol derivative recognition. A third residue, E283 in TMS9, seems to be necessary for correct membrane folding of the transporter.

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Eda, Shima, Hisayuki Mitsui, and Kiwamu Minamisawa. "Involvement of the SmeAB Multidrug Efflux Pump in Resistance to Plant Antimicrobials and Contribution to Nodulation Competitiveness in Sinorhizobium meliloti." Applied and Environmental Microbiology 77, no. 9 (March 11, 2011): 2855–62. http://dx.doi.org/10.1128/aem.02858-10.

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ABSTRACTThe contributions of multicomponent-type multidrug efflux pumps to antimicrobial resistance and nodulation ability inSinorhizobium melilotiwere comprehensively analyzed. Computational searches identified genes in theS. melilotistrain 1021 genome encoding 1 pump from the ATP-binding cassette family, 3 pumps from the major facilitator superfamily, and 10 pumps from the resistance-nodulation-cell division family, and subsequently, these genes were deleted either individually or simultaneously. Antimicrobial susceptibility tests demonstrated that deletion of thesmeABpump genes resulted in increased susceptibility to a range of antibiotics, dyes, detergents, and plant-derived compounds and, further, that specific deletion of thesmeCDorsmeEFgenes in a ΔsmeABbackground caused a further increase in susceptibility to certain antibiotics. Competitive nodulation experiments revealed that thesmeABmutant was defective in competing with the wild-type strain for nodulation. The introduction of a plasmid carryingsmeABinto thesmeABmutant restored antimicrobial resistance and nodulation competitiveness. These findings suggest that the SmeAB pump, which is a major multidrug efflux system ofS. meliloti, plays an important role in nodulation competitiveness by mediating resistance toward antimicrobial compounds produced by the host plant.

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Lehrer, Mark, and Stefan Schmid. "Family firms taking surprising risks: building success on conservative values." Journal of Business Strategy 40, no. 5 (September 3, 2019): 21–27. http://dx.doi.org/10.1108/jbs-06-2018-0116.

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Purpose This paper aims to explore hidden wellsprings of risk-taking in family firms. Design/methodology/approach The high tolerance for risk shown repeatedly by the famous family firm Hipp of Germany is documented. Three major risk-taking episodes at Hipp are examined. Findings Counterintuitively, conservative values were actually a major facilitator of risk-taking at Hipp. Research limitations/implications The ramifications for other family firms, especially in Germany’s so-called Mittelstand, are examined. An open question is whether the relevant scope of the foregoing analysis may be confined to national contexts like German Mittelstand with its highly developed sector of family firms. Practical implications Contrary to received wisdom, family firms with conservative values may actually have certain advantages in their capacity not only to assume certain types of risks but also to mitigate such risks. Especially the communitarian embeddedness of such values may provide a layer of risk mitigation. Social implications At least in some countries, such as Germany, family firms are indeed willing to engage in substantial risk-taking. With their approach of combining conservative values and risk-taking, they contribute to considerable wealth and societal development. Originality/value Conservatism in management and risk-taking propensity are usually thought of as antipodes. However, it is necessary to distinguish between conservatism (which usually equates to risk aversion) and conservative values (which, as shown, may be highly compatible with a willingness to engage and succeed in risky undertakings).

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Meena, Varsha, Shivani Sharma, Gazaldeep Kaur, Bhupinder Singh, and Ajay Kumar Pandey. "Diverse Functions of Plant Zinc-Induced Facilitator-like Transporter for Their Emerging Roles in Crop Trait Enhancement." Plants 11, no. 1 (December 30, 2021): 102. http://dx.doi.org/10.3390/plants11010102.

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The major facilitator superfamily (MFS) is a large and diverse group of secondary transporters found across all kingdoms of life. Zinc-induced facilitator-like (ZIFL) transporters are the MFS family members that function as exporters driven by the antiporter-dependent processes. The presence of multiple ZIFL transporters was shown in various plant species, as well as in bryophytes. However, only a few ZIFLs have been functionally characterized in plants, and their localization has been suggested to be either on tonoplast or at the plasma membrane. A subset of the plant ZIFLs were eventually characterized as transporters due to their specialized role in phytosiderophores efflux and auxin homeostasis, and they were also proven to impart tolerance to micronutrient deficiency. The emerging functions of ZIFL proteins highlight their role in addressing important traits in crop species. This review aims to provide insight into and discuss the importance of plant ZIFL in various tissue-specific functions. Furthermore, a spotlight is placed on their role in mobilizing essential micronutrients, including iron and zinc, from the rhizosphere to support plant survival. In conclusion, in this paper, we discuss the functional redundancy of ZIFL transporters to understand their roles in developing specific traits in crop.

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Xiao, Qingjie, Mengxue Xu, Weiwei Wang, Tingting Wu, Weizhe Zhang, Wenming Qin, and Bo Sun. "Utilization of AlphaFold2 to Predict MFS Protein Conformations after Selective Mutation." International Journal of Molecular Sciences 23, no. 13 (June 29, 2022): 7235. http://dx.doi.org/10.3390/ijms23137235.

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The major facilitator superfamily (MFS) is the largest secondary transporter family and is responsible for transporting a broad range of substrates across the biomembrane. These proteins are involved in a series of conformational changes during substrate transport. To decipher the transport mechanism, it is necessary to obtain structures of these different conformations. At present, great progress has been made in predicting protein structure based on coevolutionary information. In this study, AlphaFold2 was used to predict different conformational structures for 69 MFS transporters of E. coli after the selective mutation of residues at the interface between the N- and C-terminal domains. The predicted structures for these mutants had small RMSD values when compared to structures obtained using X-ray crystallography, which indicates that AlphaFold2 predicts the structure of MSF transporters with high accuracy. In addition, different conformations of other transporter family proteins have been successfully predicted based on mutation methods. This study provides a structural basis to study the transporting mechanism of the MFS transporters and a method to probe dynamic conformation changes of transporter family proteins when performing their function.

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Xiang, Qin, Yanna Cao, Hongbo Xu, Zhijian Yang, Liang Tang, Ju Xiang, Jianming Li, Hao Deng, and Lamei Yuan. "Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy." Journal of Ophthalmology 2021 (August 17, 2021): 1–5. http://dx.doi.org/10.1155/2021/6684045.

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Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

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Grousd, Jennifer A., Anthony Richardson, Vaughn Cooper, and John F. Alcorn. "Adhesion requirements of methicillin-resistant Staphylococcus aureus in bacterial pneumonia and influenza super-infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.49. http://dx.doi.org/10.4049/jimmunol.202.supp.190.49.

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Abstract In the respiratory tract, Staphylococcus aureus is associated with infections ranging from asymptomatic colonization to severe necrotizing pneumonia. While staphylococcal pneumonia has always been highly associated with influenza infections in young children and the elderly, it has emerged as the major cause of pneumonia associated with influenza since the 2009 H1N1 pandemic. Despite the clinical relevance of methicillin-resistant S. aureus (MRSA), few studies have examined bacterial factors of MRSA in pneumonia and how preceding influenza may alter the behavior of MRSA in the lung. Successful establishment of infection by bacterial pathogens requires adhesion to host cells. Staphylococcal species express a broad range of surface proteins that are involved in adhesion to host cells, known as the MSCRAMM family. MSCRAMM proteins have known roles in upper respiratory tract colonization, however their role in the lung is unknown. Preliminary data suggest that the MSCRAMM family members are important within the lung as MRSA lacking all MSCRAMMs (ΔsrtA) has decreased immune infiltrate in influenza super-infection. Additionally, the MSCRAMM family member SdrD has a role in both bacterial adherence as well as epithelial integrity and immunity in MRSA pneumonia and super-infection. Mice infected with MRSA lacking SdrD (ΔsdrD) have lower bacterial burden and increased expression of epithelial antimicrobial peptides cathelicidin and Reg3g with no difference in overall inflammation measured by immune infiltrate and pro-inflammatory cytokine levels. This suggests that MSCRAMM family members play a role in infection within the lung in both MRSA pneumonia and super-infection and can alter the immune response.

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Parakh, Sehgal. "A Subtractive Proteomics Approach to Identify Putative Drug Targets Against Parasitic Species." International Journal of Current Research and Review 14, no. 15 (2022): 33–39. http://dx.doi.org/10.31782/ijcrr.2022.141501.

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Introduction: Parasitic diseases affecting humans continue to be the leading cause of morbidity as well as mortality, particularly in tropical and subtropical countries. With the rise of multi-drug resistant forms of many diseases, it has become increasingly important to develop new strategies to identify alternative drug targets. One such strategy for analysis of protein sequences of pathogen that can provide useful insight and markers for drug target identification is the Subtractive Proteomics Approach (SPA). In this dataset between the host and pathogen proteome is subtracted and analysed which provides information pertaining to a set of proteins that are likely to be essential to the pathogen but absent in the host. The subtractive Proteomics Approach (SPA) is one of the most efficient methods which includes the use of various precise software databases. Aim: SPA analysis was to predict putative drug targets in parasitic species Leishmania major, Plasmodium falciparum, Trypanosoma brucei and Trypanosoma cruzi. Methods: Common proteins of these species were predicted using Transporter Database 2.0. Common protein was analyzed by BlastP tool that predicted proteins that are non-homologous to homo sapiens. Database of Essential Genes (DEG) database was used to predict essential proteins for parasites and results were subjected to CELLO tool to identify the subcellular localization of important protein targets. Prosite database identified important protein families and patterns which were present in drug targets. Results: Drug targets identified in parasitic species Leishmania major, Plasmodium falciparum, Trypanosoma brucei and Trypanosoma cruzi are mitochondrial Carrier family, Major Facilitator Superfamily, Sulfate Permease Family, P-type ATPase Superfamily and Major Intrinsic Protein Family respectively. Conclusion: Screening of drug targets using SPA approach has identified major drug targets in parasitic species and which are not present in human and can be investigated further by computational drug designing and systems biology approach.

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Li, Chunwei, Qiuye You, and Panfeng Zhao. "Genome-wide identification and characterization of SPX-domain-containing protein gene family in Solanum lycopersicum." PeerJ 9 (December 22, 2021): e12689. http://dx.doi.org/10.7717/peerj.12689.

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The SYG1, PHO81, and XPR1 (SPX) domain is named after the suppressor of yeast gpa1 (Syg1), yeast phosphatase (Pho81) and the human Xenotropic and Polytrophic Retrovirus receptor1 (XPR1). SPX-domain-containing proteins play pivotal roles in maintaining phosphate ions (Pi) homeostasis in plant. This study was to genome-wide identification and analysis of Solanum lycopersicum SPX-domain-containing protein gene family. The Solanum lycopersicum genome contains 19 SPX-domain-containing protein genes. These SPX-domain-containing protein genes were located in seven of the 12 chromosomes. According to the different conserved domains, the proteins encoded by those genes could be divided into four SPX-domain-containing protein families, which included SPX Family, SPX-ERD1/XPR1/SYG1(SPX-EXS) Family, SPX-Major Facilitator Superfamily (SPX-MFS) Family and SPX-Really Interesting New Gene (SPX-RING) Family. Phylogenetic analysis of SPX-domain-containing protein genes in Arabidopsis thaliana, Solanum tuberosum, Capsicum annuum and Solanum lycopersicum classified these genes into eight clades. Expression profiles derived from transcriptome (RNA-seq) data analysis showed 19 SPX-domain-containing protein genes displayed various expression patterns. SPX-domain-containing protein may play different roles in phosphate nutrition of Solanum lycopersicum different tissues and development stages. And, this study can provide the selection of candidate genes for functional research and genome editing in Solanum lycopersicum phosphate ions (Pi) nutrition.

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Vardy, Eyal, Sonia Steiner-Mordoch, and Shimon Schuldiner. "Characterization of Bacterial Drug Antiporters Homologous to Mammalian Neurotransmitter Transporters." Journal of Bacteriology 187, no. 21 (November 1, 2005): 7518–25. http://dx.doi.org/10.1128/jb.187.21.7518-7525.2005.

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ABSTRACT Multidrug transporters are ubiquitous proteins, and, based on amino acid sequence similarities, they have been classified into several families. Here we characterize a cluster of archaeal and bacterial proteins from the major facilitator superfamily (MFS). One member of this family, the vesicular monoamine transporter (VMAT) was previously shown to remove both neurotransmitters and toxic compounds from the cytoplasm, thereby conferring resistance to their effects. A BLAST search of the available microbial genomes against the VMAT sequence yielded sequences of novel putative multidrug transporters. The new sequences along with VMAT form a distinct cluster within the dendrogram of the MFS, drug-proton antiporters. A comparison with other proteins in the family suggests the existence of a potential ion pair in the membrane domain. Three of these genes, from Mycobacterium smegmatis, Corynebacterium glutamicum, and Halobacterium salinarum, were cloned and functionally expressed in Escherichia coli. The proteins conferred resistance to fluoroquinolones and chloramphenicol (at concentrations two to four times greater than that of the control). Measurement of antibiotic accumulation in cells revealed proton motive force-dependent transport of those compounds.

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Burgdorf, Julia, and Alicia Arbaje. "Family Caregiver Training During Medicare Home Health Care: Clinician Perspectives." Innovation in Aging 5, Supplement_1 (December 1, 2021): 533. http://dx.doi.org/10.1093/geroni/igab046.2052.

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Abstract During Medicare home health care, providers often rely on family caregivers to help meet patients’ care needs. Beginning in 2018, CMS requires home health agencies to provide training to family caregivers. This qualitative study is the first research to examine current patterns of family caregiver training, and related facilitators and barriers, during Medicare-funded home health care. We conducted semi-structured key informant interviews with home health nurses and physical therapists (n=19) from 4 diverse agencies, then performed thematic analysis of interview transcripts using a hybrid inductive and deductive coding approach. Clinicians described family caregiver education as a dynamic and cyclical process: simultaneously providing patient care, training family caregivers, and gathering additional information about patient needs and caregiver capabilities, then adjusting the care plan accordingly. We present a model of this cyclic process and describe its four major stages: Initial Assessment, Education, Reassessment, and Adjustment. Additionally, clinicians identified a range of structural, individual, and interpersonal factors which impact their ability to successfully train family caregivers. We define each factor and, using illustrative quotes from our interviews, elucidate its role as a facilitator and/or barrier to clinicians’ educational efforts. Findings provide the first model of caregiver training during home health care and highlight policy and practice changes to better support clinicians in these efforts; including greater visit flexibility, access to more experienced clinical mentors, and standardized caregiver assessment tools designed for this unique care setting.

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Perland, Emelie, Sonchita Bagchi, Axel Klaesson, and Robert Fredriksson. "Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression." Open Biology 7, no. 9 (September 2017): 170142. http://dx.doi.org/10.1098/rsob.170142.

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Solute carriers (SLCs) are vital as they are responsible for a major part of the molecular transport over lipid bilayers. At present, there are 430 identified SLCs, of which 28 are called atypical SLCs of major facilitator superfamily (MFS) type. These are MFSD1, 2A, 2B, 3, 4A, 4B, 5, 6, 6 L, 7, 8, 9, 10, 11, 12, 13A, 14A and 14B; SV2A, SV2B and SV2C; SVOP and SVOPL; SPNS1, SPNS2 and SPNS3; and UNC93A and UNC93B1. We studied their fundamental properties, and we also included CLN3, an atypical SLC not yet belonging to any protein family (Pfam) clan, because its involvement in the same neuronal degenerative disorders as MFSD8. With phylogenetic analyses and bioinformatic sequence comparisons, the proteins were divided into 15 families, denoted atypical MFS transporter families (AMTF1-15). Hidden Markov models were used to identify orthologues from human to Drosophila melanogaster and Caenorhabditis elegans . Topology predictions revealed 12 transmembrane segments (for all except CLN3), corresponding to the common MFS structure. With single-cell RNA sequencing and in situ proximity ligation assay on brain cells, co-expressions of several atypical SLCs were identified. Finally, the transcription levels of all genes were analysed in the hypothalamic N25/2 cell line after complete amino acid starvation, showing altered expression levels for several atypical SLCs.

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Felder, Thomas, Edith Bogengruber, Sandra Tenreiro, Adi Ellinger, Isabel Sá-Correia, and Peter Briza. "Dtr1p, a Multidrug Resistance Transporter of the Major Facilitator Superfamily, Plays an Essential Role in Spore Wall Maturation in Saccharomyces cerevisiae." Eukaryotic Cell 1, no. 5 (October 2002): 799–810. http://dx.doi.org/10.1128/ec.1.5.799-810.2002.

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ABSTRACT The de novo formation of multilayered spore walls inside a diploid mother cell is a major landmark of sporulation in the yeast Saccharomyces cerevisiae. Synthesis of the dityrosine-rich outer spore wall takes place toward the end of this process. Bisformyl dityrosine, the major building block of the spore surface, is synthesized in a multistep process in the cytoplasm of the prospores, transported to the maturing wall, and polymerized into a highly cross-linked macromolecule on the spore surface. Here we present evidence that the sporulation-specific protein Dtr1p (encoded by YBR180w) plays an important role in spore wall synthesis by facilitating the translocation of bisformyl dityrosine through the prospore membrane. DTR1 was identified in a genome-wide screen for spore wall mutants. The null mutant accumulates unusually large amounts of bisformyl dityrosine in the cytoplasm and fails to efficiently incorporate this precursor into the spore surface. As a result, many mutant spores have aberrant surface structures. Dtr1p, a member of the poorly characterized DHA12 (drug:H+ antiporter with 12 predicted membrane spans) family, is localized in the prospore membrane throughout spore maturation. Transport by Dtr1p may not be restricted to its natural substrate, bisformyl dityrosine. When expressed in vegetative cells, Dtr1p renders these cells slightly more resistant against unrelated toxic compounds, such as antimalarial drugs and food-grade organic acid preservatives. Dtr1p is the first multidrug resistance protein of the major facilitator superfamily with an assigned physiological role in the yeast cell.

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Grytsyk, Natalia, Ana Filipa Santos Seiça, Junichi Sugihara, H. Ronald Kaback, and Petra Hellwig. "Arg302 governs the pKa of Glu325 in LacY." Proceedings of the National Academy of Sciences 116, no. 11 (February 21, 2019): 4934–39. http://dx.doi.org/10.1073/pnas.1820744116.

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Lactose permease is a paradigm for the major facilitator superfamily, the largest family of ion-coupled membrane transport proteins known at present. LacY carries out the coupled stoichiometric symport of a galactoside with an H+, using the free energy released from downhill translocation of H+ to drive accumulation of galactosides against a concentration gradient. In neutrophilic Escherichia coli, internal pH is kept at ∼7.6 over the physiological range, but the apparent pK (pKapp) for galactoside binding is 10.5. Surface-enhanced infrared absorption spectroscopy (SEIRAS) demonstrates that the high pKa is due to Glu325 (helix X), which must be protonated for LacY to bind galactoside effectively. Deprotonation is also obligatory for turnover, however. Here, we utilize SEIRAS to study the effect of mutating residues in the immediate vicinity of Glu325 on its pKa. The results are consistent with the idea that Arg302 (helix IX) is important for deprotonation of Glu325.

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Halsall, John R., Michael J. Milner, and Lorna A. Casselton. "Three Subfamilies of Pheromone and Receptor Genes Generate Multiple B Mating Specificities in the Mushroom Coprinus cinereus." Genetics 154, no. 3 (March 1, 2000): 1115–23. http://dx.doi.org/10.1093/genetics/154.3.1115.

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Abstract The B mating type locus of the basidiomycete Coprinus cinereus encodes a large family of lipopeptide pheromones and their seven transmembrane domain receptors. Here we show that the B42 locus, like the previously described B6 locus, derives its unique specificity from nine multiallelic genes that are organized into three subgroups each comprising a receptor and two pheromone genes. We show that the three genes within each group are kept together as a functional unit by being embedded in an allele-specific DNA sequence. Using a combination of sequence analysis, Southern blotting, and DNA-mediated transformation with cloned genes, we demonstrate that different B loci may share alleles of one or two groups of genes. This is consistent with the prediction that the three subgroups of genes are functionally redundant and that it is the different combinations of their alleles that generate the multiple B mating specificities found in nature. The B42 locus was found to contain an additional gene, mfs1, that encodes a putative multidrug transporter belonging to the major facilitator family. In strains with other B mating specificities, this gene, whose functional significance was not established, lies in a region of shared homology flanking the B locus.

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Wright, Ernest M., Chiara Ghezzi, and Donald D. F. Loo. "Novel and Unexpected Functions of SGLTs." Physiology 32, no. 6 (November 2017): 435–43. http://dx.doi.org/10.1152/physiol.00021.2017.

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It has been 30 years since the intestinal sodium glucose cotransporter SGLT1 was cloned, and, in the intervening years, there have been many advances that have influenced physiology and medicine. Among the first was that SGLT1 is the founding member of the human gene family SLC5, containing 11 diverse transporters and a glucose sensor. Equally surprising was that SGLTs are members of a structural family of cotransporters and exchangers in different gene families. This led to the conclusion that these proteins operate by a mechanism where transport involves the opening and closing of external and internal gates. The mechanism is shared by a wide variety of transporters in different structural families, e.g., the human facilitated glucose transporters (SLC2) in the huge major facilitator superfamily (MFS). Not surprising is the finding that mutations in Sglt genes cause the rare diseases glucose-galactose-malabsorption (GGM) and familial renal glucosuria (FRG). However, it was not envisaged that SGLT inhibitors would be used to treat diabetes mellitus, and these drugs may be able to treat cancer. Finally, in 2017, we have just learned that SGLT1 may be required to resist infection and to avoid recurrent pregnancy loss.

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Miserachs, Mar, David B. Nicholas, Anthony R. Otley, and Vicky Lee Ng. "Health-Related Quality of Life after Pediatric Liver Transplantation: A Qualitative Analysis of the Perspectives of Health Care Providers." Canadian Journal of Gastroenterology and Hepatology 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/5274923.

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With improved survival outcomes after pediatric liver transplantation (LT), health-related quality of life (HRQoL) is an important outcome metric. Understanding the elements contributing to HRQoL after LT in children would enable more targeted strategies towards optimizing best outcomes. This qualitative study aimed to explore health care providers (HCP) perceptions about HRQoL after pediatric LT. Thirteen experienced HCP participated in two focus group discussions. Data analysis via a thematic analysis approach revealed 4 major themes: “LT as a facilitator of better HRQoL,” “coping and adapting to LT,” “living with a transplanted liver,” and “the family context.” HCP identified elements that both enhance (improved physical health, peer relationship, and activities of daily living) and challenge (need for immunosuppression, transplant follow-up, and restrictions) the multidimensional domains of HRQoL. HCP perceived LT to be a stressful life-changing event for children and their families. Patients and their parents’ ability to cope and adjust positively to LT was perceived as a key contributor to better HRQoL. HCP perspective highlights the importance of promoting psychosocial support and a family-centered care delivery model towards the overarching goal of optimizing durable outcomes.

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Marrer, Estelle, Karen Schad, Andreas T. Satoh, Malcolm G. P. Page, Maggie M. Johnson, and Laura J. V. Piddock. "Involvement of the Putative ATP-Dependent Efflux Proteins PatA and PatB in Fluoroquinolone Resistance of a Multidrug-Resistant Mutant of Streptococcus pneumoniae." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 685–93. http://dx.doi.org/10.1128/aac.50.2.685-693.2006.

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ABSTRACT The multidrug-resistant mutant Streptococcus pneumoniae M22 constitutively overexpresses two genes (patA and patB) that encode proteins homologous to known efflux proteins belonging to the ABC transporter family. It is shown here that PatA and PatB were strongly induced by quinolone antibiotics and distamycin in fluoroquinolone-sensitive strains. PatA was very important for growth of S. pneumoniae, and it could not be disrupted in strain M22. PatB appeared to control metabolic activity, particularly in amino acid biosynthesis, and it may have a pivotal role in coordination of the response to quinolone antibiotics. The induction of PatA and PatB by antibiotics showed a pattern similar to that exhibited by SP1861, a homologue of ABC-type transporters of choline and other osmoprotectants. A second group of quinolone-induced transporter genes comprising SP1587 and SP0287, which are homologues of, respectively, oxalate/formate antiporters and xanthine or uracil permeases belonging to the major facilitator family, showed a different pattern of induction by other antibiotics. There was no evidence for the involvement of PmrA, the putative proton-dependent multidrug transporter that has been implicated in norfloxacin resistance, in the response to quinolone antibiotics in either the resistant mutant or the fluoroquinolone-sensitive strains.

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Condemine, Guy. "Characterization of SotA and SotB, TwoErwinia chrysanthemi Proteins Which Modify Isopropyl-β-d-Thiogalactopyranoside and Lactose Induction of the Escherichia coli lac Promoter". Journal of Bacteriology 182, № 5 (1 березня 2000): 1340–45. http://dx.doi.org/10.1128/jb.182.5.1340-1345.2000.

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ABSTRACT The expression, in Escherichia coli, of variants of theErwinia chrysanthemi secretion genes outB andoutS under the Ptac promoter is toxic to the cells. During attempts to clone E. chrysanthemi genes able to suppress this toxicity, I identified two genes, sotA andsotB, whose products are able to reduce the isopropyl-β-d-thiogalactopyranoside (IPTG) induction of the E. coli lac promoter. SotA and SotB belong to two different families of the major facilitator superfamily. SotA is a member of the sugar efflux transporter family, while SotB belongs to the multidrug efflux family. The results presented here suggest that SotA and SotB are sugar efflux pumps. SotA reduces the intracellular concentration of IPTG, lactose, and arabinose. SotB reduces the concentration of IPTG, lactose, and melibiose. Expression ofsotA and sotB is not regulated by their substrates, but sotA is activated by the cyclic AMP receptor protein (CRP), while sotB is repressed by CRP. Lactose is weakly toxic for E. chrysanthemi. This toxicity is increased in a sotB mutant which cannot efficiently efflux lactose. This first evidence for a physiological role of sugar efflux proteins suggests that their function could be to reduce the intracellular concentration of toxic sugars or sugar metabolites.

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46

Kumar, Sujeet, and William T. Doerrler. "Members of the Conserved DedA Family Are Likely Membrane Transporters and Are Required for Drug Resistance in Escherichia coli." Antimicrobial Agents and Chemotherapy 58, no. 2 (November 25, 2013): 923–30. http://dx.doi.org/10.1128/aac.02238-13.

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ABSTRACTBacterial resistance to antibiotics and biocides is an increasing public health problem. Genes encoding integral membrane proteins belonging to the DedA family are present in most bacterial genomes, includingEscherichia coli. AnE. colistrain lacking partially redundant DedA family genesyqjAandyghB(strain BC202) displays temperature sensitivity and cell division defects. These phenotypes can be corrected by overexpression ofmdfA, an Na+-K+/H+antiporter of the major facilitator superfamily. We show that BC202 is hypersensitive to several biocides and cationic compounds that are known substrates of several multidrug resistance transporters, including MdfA, EmrE, and AcrB. The introduction of deletions of genes encoding these drug transporters into BC202 results in additional sensitivity. Expression of wild-typeyghBoryqjAcan restore drug resistance, but this is eliminated upon mutation of two membrane-embedded acidic amino acids (E39 or D51 in either protein). This dependence upon membrane-embedded acidic amino acids is a hallmark of proton-dependent antiporters. Overexpression ofmdfAin BC202 or artificially restoring proton motive force (PMF) restores wild-type resistance to substrates of MdfA as well as other drug resistance transporters such as EmrE and AcrAB. These results suggest that YqjA and YghB may be membrane transporters required for PMF-dependent drug efflux inE. coli.

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Zhao, Zeqi, Mengdi Li, Weiwei Xu, Ji-Hong Liu, and Chunlong Li. "Genome-Wide Identification of NRT Gene Family and Expression Analysis of Nitrate Transporters in Response to Salt Stress in Poncirus trifoliata." Genes 13, no. 7 (June 22, 2022): 1115. http://dx.doi.org/10.3390/genes13071115.

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The uptake and transportation of nitrate play a crucial role in plant growth and development. These processes mostly depend on nitrate transporters (NRT), which guarantee the supplement of nutrition in the plant. In this study, genes encoding NRT with Major Facilitator Superfamily (MFS) domain were identified in trifoliate orange (Poncirus trifoliata (L.) Raf.). Totally, 56 NRT1s, 6 NRT2s, and 2 NAR2s were explored. The bioinformation analysis, including protein characteristics, conserved domain, motif, phylogenetic relationship, cis-acting element, and synteny correlation, indicated the evolutionary conservation and functional diversity of NRT genes. Additionally, expression profiles of PtrNRTs in different tissues demonstrated that NRT genes possessed spatio-temporal expression specificity. Further, the salt condition was certified to induce the expression of some NRT members, like PtrNPF2.1, PtrNPF7.4, and PtrNAR2.1, proposing the potential role of these NRTs in salt stress response. The identification of NRT genes and the expression pattern analysis in various tissues and salt stress lay a foundation for future research between nitrogen transport and salt resistance in P. trifoliata.

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48

Dhaoui, Manel, Françoise Auchère, Pierre-Louis Blaiseau, Emmanuel Lesuisse, Ahmed Landoulsi, Jean-Michel Camadro, Rosine Haguenauer-Tsapis, and Naïma Belgareh-Touzé. "Gex1 is a yeast glutathione exchanger that interferes with pH and redox homeostasis." Molecular Biology of the Cell 22, no. 12 (June 15, 2011): 2054–67. http://dx.doi.org/10.1091/mbc.e10-11-0906.

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In the yeast Saccharomyces cerevisiae, glutathione plays a major role in heavy metal detoxification and protection of cells against oxidative stress. We show that Gex1 is a new glutathione exchanger. Gex1 and its paralogue Gex2 belong to the major facilitator superfamily of transporters and display similarities to the Aft1-regulon family of siderophore transporters. Gex1 was found mostly at the vacuolar membrane and, to a lesser extent, at the plasma membrane. Gex1 expression was induced under conditions of iron depletion and was principally dependent on the iron-responsive transcription factor Aft2. However, a gex1Δ gex2Δ strain displayed no defect in known siderophore uptake. The deletion mutant accumulated intracellular glutathione, and cells overproducing Gex1 had low intracellular glutathione contents, with glutathione excreted into the extracellular medium. Furthermore, the strain overproducing Gex1 induced acidification of the cytosol, confirming the involvement of Gex1 in proton transport as a probable glutathione/proton antiporter. Finally, the imbalance of pH and glutathione homeostasis in the gex1Δ gex2Δ and Gex1-overproducing strains led to modulations of the cAMP/protein kinase A and protein kinase C1 mitogen-activated protein kinase signaling pathways.

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Xie, Tao, Wenjing Yang, Xin Chen, Hao Rong, Youping Wang, and Jinjin Jiang. "Genome-Wide Identification and Expressional Profiling of the Metal Tolerance Protein Gene Family in Brassica napus." Genes 13, no. 5 (April 26, 2022): 761. http://dx.doi.org/10.3390/genes13050761.

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The Cation Diffusion Facilitator (CDF) family, also named Metal Tolerance Protein (MTP), is one of the gene families involved in heavy metal transport in plants. However, a comprehensive study of MTPs in Brassica napus has not been reported yet. In the present study, we identified 33 BnMTP genes from the rapeseed genome using bioinformatic analyses. Subsequently, we analyzed the phylogenetic relationship, gene structure, chromosome distribution, conserved domains, and motifs of the BnMTP gene family. The 33 BnMTPs were phylogenetically divided into three major clusters (Zn-CDFs, Fe/Zn-CDFs, and Mn-CDFs) and seven groups (group 1, 5, 6, 7, 8, 9, and 12). The structural characteristics of the BnMTP members were similar in the same group, but different among groups. Evolutionary analysis indicated that the BnMTP gene family mainly expanded through whole-genome duplication (WGD) and segmental duplication events. Moreover, the prediction of cis-acting elements and microRNA target sites suggested that BnMTPs might be involved in plant growth, development, and stress responses. In addition, we found the expression of 24 BnMTPs in rapeseed leaves or roots could respond to heavy metal ion treatments. These results provided an important basis for clarifying the biological functions of BnMTPs, especially in heavy metal detoxification, and will be helpful in the phytoremediation of heavy metal pollution in soil.

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50

Xie, Tao, Wenjing Yang, Xin Chen, Hao Rong, Youping Wang, and Jinjin Jiang. "Genome-Wide Identification and Expressional Profiling of the Metal Tolerance Protein Gene Family in Brassica napus." Genes 13, no. 5 (April 26, 2022): 761. http://dx.doi.org/10.3390/genes13050761.

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The Cation Diffusion Facilitator (CDF) family, also named Metal Tolerance Protein (MTP), is one of the gene families involved in heavy metal transport in plants. However, a comprehensive study of MTPs in Brassica napus has not been reported yet. In the present study, we identified 33 BnMTP genes from the rapeseed genome using bioinformatic analyses. Subsequently, we analyzed the phylogenetic relationship, gene structure, chromosome distribution, conserved domains, and motifs of the BnMTP gene family. The 33 BnMTPs were phylogenetically divided into three major clusters (Zn-CDFs, Fe/Zn-CDFs, and Mn-CDFs) and seven groups (group 1, 5, 6, 7, 8, 9, and 12). The structural characteristics of the BnMTP members were similar in the same group, but different among groups. Evolutionary analysis indicated that the BnMTP gene family mainly expanded through whole-genome duplication (WGD) and segmental duplication events. Moreover, the prediction of cis-acting elements and microRNA target sites suggested that BnMTPs might be involved in plant growth, development, and stress responses. In addition, we found the expression of 24 BnMTPs in rapeseed leaves or roots could respond to heavy metal ion treatments. These results provided an important basis for clarifying the biological functions of BnMTPs, especially in heavy metal detoxification, and will be helpful in the phytoremediation of heavy metal pollution in soil.

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