scholarly journals Systematic in silico discovery of novel solute carrier-like proteins from proteomes

2021 ◽  
Author(s):  
Gergely Gyimesi ◽  
Matthias A. Hediger
Keyword(s):  
Sequence Similarity ◽  
Structural Heterogeneity ◽  
Protein Families ◽  
Systematic Analysis ◽  
Slc Transporters ◽  
Solute Carrier ◽  
The Many ◽  
Slc Transporter ◽  
Transmembrane Transporters ◽  
Similarity Searches

Solute carrier (SLC) proteins represent the largest superfamily of transmembrane transporters, the systematic analysis of which is hampered by their functional and structural heterogeneity, despite their biological importance. Based on available nomenclature systems, we suspected that many as yet unidentified SLC transporters exist in the human genome. Here, we present criteria for defining "SLC-likeness" and apply them to curate a set of "SLC-like" protein families from the Transporter Classification Database (TCDB) and Protein families (Pfam) databases. Computational sequence similarity searches then surprisingly yielded ~130 more proteins in human with SLC-like properties, compared to previous annotations. Several of these novel putative SLC transporter proteins actually have documented transport activity in the scientific literature. We complete our overview of the SLC-ome by presenting an algorithm to classify SLC-like proteins into protein families, investigating their known functions and evolutionary relationships to similar proteins from 6 other clinically relevant experimental organisms, and pinpointing structural orphans. We envision that our work will serve as a stepping stone for future studies of the biological function and the identification of the natural substrates of the many under-explored SLC transporters, as well as the development of new therapeutic applications, including strategies for personalized medicine and drug delivery.

Genetic variations in microRNA binding sites of solute carrier transporter genes as predictors of clinical outcome in colorectal cancer

2020 ◽  
Author(s):  
Petra Bendova ◽  
Barbara Pardini ◽  
Simona Susova ◽  
Jachym Rosendorf ◽  
Miloslav Levy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Messenger Rna ◽  
Drug Transport ◽  
Chemotherapy Resistance ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Nucleotide Polymorphisms ◽  
Slc Transporters ◽  
Solute Carrier ◽  
Slc Transporter

Abstract One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors like colorectal cancer (CRC) is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent interindividual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient’s survival. Using an in silico approach for functional predictions, we analyzed twenty-six miRSNPs in nine SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient’s survival. SNPs in SLCO3A1, SLC22A2, and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient’s prognosis.

scholarly journals The Identification and Evolutionary Trends of the Solute Carrier Superfamily in Arthropods

2020 ◽  
Vol 12 (8) ◽  
pp. 1429-1439
Author(s):  
Shane M Denecke ◽  
Olympia Driva ◽  
Hang Ngoc Bao Luong ◽  
Panagiotis Ioannidis ◽  
Marc Linka ◽  
...  
Keyword(s):  
Web Application ◽  
Gene Family Evolution ◽  
Rapid Expansion ◽  
Slc Transporters ◽  
Arthropod Species ◽  
A Genome ◽  
R Shiny ◽  
Solute Carrier ◽  
Slc Transporter ◽  
Systematic Identification

Abstract The solute carrier (SLC) transporter superfamily comprises an ancient and ubiquitous group of proteins capable of translocating a range of nutrients, endogenous molecules, and xenobiotics. Although the group has been the subject of intense investigation in both bacteria and mammals, its systematic identification in arthropods has not yet been undertaken. Here, we present a genome-wide identification of all 66 human SLC families in 174 arthropod species. A pipeline (SLC_id) was constructed to identify and group SLCs using a combination of hidden Markov model and BLAST searches followed by filtering based on polypeptide length and the number of transmembrane domains. Comparative analysis of the number of transporters in each family across diverse arthropod lineages was accomplished using one-way analysis of variance (ANOVA) and the Computational Analysis of gene Family Evolution (CAFE). These results suggested that many SLC families have undergone expansions or contractions in particular evolutionary lineages. Notably, the sugar transporting SLC2 family was significantly larger in insects compared with arachnids. This difference may have been complemented by a rapid expansion of the SLC60 family in arachnids which also acts on dietary sugars. Furthermore, the SLC33 family underwent a recent and drastic expansion in aphids, although the biological relevance of this expansion was not possible to infer. Information on specific SLC transporter families across arthropod species can be accessed through an R shiny web application at http://chrysalida.imbb.forth.gr : 3838/Arthropod_SLC_Database/. The present study greatly facilitates further investigation of the diverse group of SLC transporters in arthropods.

scholarly journals The genetic landscape of the human solute carrier (SLC) transporter superfamily

2019 ◽  
Vol 138 (11-12) ◽  
pp. 1359-1377 ◽  
Author(s):  
Lena Schaller ◽  
Volker M. Lauschke
Keyword(s):  
Individual Differences ◽  
Small Sample ◽  
Next Generation Sequencing Data ◽  
Human Populations ◽  
Mendelian Disease ◽  
Sequence Information ◽  
Data Set ◽  
Slc Transporters ◽  
Solute Carrier ◽  
Slc Transporter

Abstract The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.

Public Investment Criteria: Benefit-Cost Analysis for Planned Economic Growth by Stephen A. Marglin. London: George Allen & Unwin Ltd., 1967. pp.103. 22s. 6d.********** Investments for Capacity Expansion: Size, Location and Time-Phasing edited by Alan S. Manne. London: George Allen & Unwin Ltd., 1967. pp.239. 45s.Investments for Capacity Expansion: Size, Location and Time-Phasing edited by Alan S. Manne. London: George Allen & Unwin Ltd., 1967. pp.239. 45s.

1967 ◽  
Vol 7 (3) ◽  
pp. 416-420
Author(s):  
Arthur MacEwan
Keyword(s):  
Cost Benefit Analysis ◽  
Public Investment ◽  
Cost Benefit ◽  
Capacity Expansion ◽  
Point Of View ◽  
Systematic Analysis ◽  
Benefit Cost Analysis ◽  
The Government ◽  
The Many ◽  
Benefit Cost

These books are numbers 4 and 5, respectively, in the series "Studies in the Economic Development of India". The two books are interesting complements to one another, both being concerned with the analysis of projects within national plan formulation. However, they treat different sorts of problems and do so on very different levels. Marglin's Public Investment Criteria is a short treatise on the problems of cost-benefit analysis in an Indian type economy, i.e., a mixed economy in which the government accepts a large planning responsibility. The book, which is wholely theoretical, explains the many criteria needed for evaluation of projects. The work is aimed at beginning students and government officials with some training in economics. It is a clear and interesting "introduction to the special branch of economics that concerns itself with systematic analysis of investment alternatives from the point of view of a government".

scholarly journals PyMod: sequence similarity searches, multiple sequence-structure alignments, and homology modeling within PyMOL

2012 ◽  
Vol 13 (Suppl 4) ◽  
pp. S2 ◽  
Author(s):  
Emanuele Bramucci ◽  
Alessandro Paiardini ◽  
Francesco Bossa ◽  
Stefano Pascarella
Keyword(s):  
Homology Modeling ◽  
Sequence Similarity ◽  
Sequence Structure ◽  
Multiple Sequence ◽  
Similarity Searches

scholarly journals Molecular Modeling and Ligand Docking for Solute Carrier (SLC) Transporters

2013 ◽  
Vol 13 (7) ◽  
pp. 843-856 ◽  
Author(s):  
Avner Schlessinger ◽  
Natalia Khuri ◽  
Kathleen M. Giacomini ◽  
Andrej Sali
Keyword(s):  
Molecular Modeling ◽  
Ligand Docking ◽  
Slc Transporters ◽  
Solute Carrier

scholarly journals Identification of a PRC2 Accessory Subunit Required for Subtelomeric H3K27 Methylation in Neurospora crassa

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Kevin J. McNaught ◽  
Elizabeth T. Wiles ◽  
Eric U. Selker
Keyword(s):  
Neurospora Crassa ◽  
Transcriptional Repression ◽  
Sequence Similarity ◽  
Model Organism ◽  
Content Type ◽  
Polycomb Repressive Complex 2 ◽  
H3k27 Methylation ◽  
Accessory Subunit ◽  
Genomic Regions ◽  
Similarity Searches

ABSTRACT Polycomb repressive complex 2 (PRC2) catalyzes methylation of histone H3 at lysine 27 (H3K27) in genomic regions of most eukaryotes and is critical for maintenance of the associated transcriptional repression. However, the mechanisms that shape the distribution of H3K27 methylation, such as recruitment of PRC2 to chromatin and/or stimulation of PRC2 activity, are unclear. Here, using a forward genetic approach in the model organism Neurospora crassa, we identified two alleles of a gene, NCU04278, encoding an unknown PRC2 accessory subunit (PAS). Loss of PAS resulted in losses of H3K27 methylation concentrated near the chromosome ends and derepression of a subset of associated subtelomeric genes. Immunoprecipitation followed by mass spectrometry confirmed reciprocal interactions between PAS and known PRC2 subunits, and sequence similarity searches demonstrated that PAS is not unique to N. crassa. PAS homologs likely influence the distribution of H3K27 methylation and underlying gene repression in a variety of fungal lineages.

scholarly journals Slc43a3 is a regulator of free fatty acid flux

2020 ◽  
Vol 61 (5) ◽  
pp. 734-745
Author(s):  
Kathrin B. Hasbargen ◽  
Wen-Jun Shen ◽  
Yiqiang Zhang ◽  
Xiaoming Hou ◽  
Wei Wang ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Lipid Droplet ◽  
Membrane Transporters ◽  
Negative Regulator ◽  
Branched Dna ◽  
Transporter Family ◽  
Before And After ◽  
Solute Carrier ◽  
Slc Transporter ◽  
Subcutaneous Adipose

Adipocytes take up long chain FAs through diffusion and protein-mediated transport, whereas FA efflux is considered to occur by diffusion. To identify potential membrane proteins that are involved in regulating FA flux in adipocytes, the expression levels of 55 membrane transporters without known function were screened in subcutaneous adipose samples from obese patients before and after bariatric surgery using branched DNA methodology. Among the 33 solute carrier (SLC) transporter family members screened, the expression of 14 members showed significant changes before and after bariatric surgery. One of them, Slc43a3, increased about 2.5-fold after bariatric surgery. Further investigation demonstrated that Slc43a3 is highly expressed in murine adipose tissue and induced during adipocyte differentiation in primary preadipocytes and in OP9 cells. Knockdown of Slc43a3 with siRNA in differentiated OP9 adipocytes reduced both basal and forskolin-stimulated FA efflux, while also increasing FA uptake and lipid droplet accumulation. In contrast, overexpression of Slc43a3 decreased FA uptake in differentiated OP9 cells and resulted in decreased lipid droplet accumulation. Therefore, Slc43a3 seems to regulate FA flux in adipocytes, functioning as a positive regulator of FA efflux and as a negative regulator of FA uptake.

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