Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology.
TL;DR: A systematic analysis of the structural and functional aspects of heteromeric solute carriers is presented and common principles of their functional roles and structural architecture are concluded.
Abstract: Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture.
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TL;DR: In this paper, the levelized cost of energy (LCOE) of different mini-grids was compared and analyzed, and the results reveal that diesel is the most expensive technology.
Abstract: Rural communities in developing countries lack access to affordable, reliable, and sustainable forms of energy, which are essential factors for improving living conditions. These communities rely on diesel and kerosene, which are highly polluting compared to renewable energy technologies, to satisfy their energy needs. In this study, hybrid renewable energy systems (HRESs) have been analyzed, which are designed to overcome the fluctuating nature of renewables, for off-grid electrification. The results of this study—which covers many countries and examples—show that the successful integration of HRES is influenced by factors such as government support—and community organization — which is essential to keep these systems operating over the project lifetime. The levelized cost of energy (LCOE) of different mini-grids was compared and analyzed. The results reveal that by comparing the LCOE range of diesel (between USD 0.92/kWh and USD 1.30/kWh), solar photovoltaic (USD 0.40/kWh and USD 0.61/kWh), and hybrid solar photovoltaic/diesel (USD 0.54/kWh to USD 0.77/kWh), diesel is the most expensive technology. Additionally, the study addressed barriers that can hinder the implementation of mini-grids, such as lack of supportive policies and high capital cost. However, governments’ incentives are instrumental in lowering capital costs. These results are of particular importance for developing countries, where electricity supply via HRES is often quicker and cheaper than grid extension. The insights from this paper are a good starting point for in-depth research on optimal local design and ownership models, which can help accelerate the implementation, and lower the costs of sustainable electricity supply in remote areas.
105 citations
TL;DR: This work was supported in part by the Spanish Ministry of Science and Innovation, Grants SAF2009-12606-C02-01 (M.P.) and BP-B2008-00239 (X.C.) and by the computer resources provided by the Red Espanola de Supercomputacion.
Abstract: This work was supported in part by the Spanish Ministry of Science and
Innovation, Grants SAF2009-12606-C02-01 (M.P.), BFU2008-04637 (J.L.V.-I.),
and BFU2009-09268 (I.F., X.C.), by the European Commission Frame Program
7 Grant 201924 (EDICT; M.P. and L.K.), by Consolider E-Science Project and
Fundacion Marcelino Botin (M.O.), and by the computer resources provided
by the Red Espanola de Supercomputacion (M.P.). Additional support from
Generalitat de Catalunya SGR2009-1355 (M.P.) and BP-B2008-00239 (X.C.)
is also acknowledged.
37 citations
01 Jan 1997
TL;DR: It is concluded that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.
Abstract: All affected patients in four families with autosomal dominant familial renal tubular acidosis (dRTA) were heterozygous for mutations in their red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members studied. The mutation Arg589--> His was present in two families, while Arg589--> Cys and Ser613--> Phe changes were found in the other families. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Arg589 mutations had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the Ser613--> Phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activity. We conclude that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.
18 citations
TL;DR: The Opinion paper is devoted to the specificity of α-amylase (EC 3.2.1.1) and its occurrence in the CAZy database and invites the scientific community to think about that with a mind open to changes and to consider the seemingly unambiguous question in the title as one that may not have a simple answer.
Abstract: Abstract The CAZy database is a web-server for sequence-based classification of carbohydrate-active enzymes that has become the worldwide and indispensable tool for scientists engaged in this research field. It was originally created in 1991 as a classification of glycoside hydrolases (GH) and currently, this section of CAZy represents its largest part counting 172 GH families. The present Opinion paper is devoted to the specificity of α-amylase (EC 3.2.1.1) and its occurrence in the CAZy database. Among the 172 defined GH families, four, i.e. GH13, GH57, GH119 and GH126, may be considered as the α-amylase GH families. This view reflects a historical background and traditions widely accepted during the previous decades with respect to the chronology of creating the individual GH families. It obeys the phenomenon that some amylolytic enzymes, which were used to create the individual GH families and were originally known as α-amylases, according to current knowledge from later, more detailed characterization, need not necessarily represent genuine α-amylases. Our Opinion paper was therefore written in an effort to invite the scientific community to think about that with a mind open to changes and to consider the seemingly unambiguous question in the title as one that may not have a simple answer.
16 citations
TL;DR: In this paper, the authors used GC-MS and LC-MS for metabolic screening of Xenopus laevis oocytes expressing various human amino acid transporters incubated in complex media to establish their comprehensive substrate profiles.
Abstract: Amino acid transporters play a vital role in metabolism and nutrient signaling pathways. Typically, transport activity is investigated using single substrates and competing amounts of other amino acids. We used GC-MS and LC-MS for metabolic screening of Xenopus laevis oocytes expressing various human amino acid transporters incubated in complex media to establish their comprehensive substrate profiles. For most transporters, amino acid selectivity matched reported substrate profiles. However, we could not detect substantial accumulation of cationic amino acids by SNAT4 and ATB0,+ in contrast to previous reports. In addition, comparative substrate profiles of two related sodium neutral amino acid transporters known as SNAT1 and SNAT2, revealed the latter as a significant leucine accumulator. As a consequence, SNAT2, but not SNAT1, was shown to be an effective activator of the eukaryotic cellular growth regulator mTORC1. We propose, that metabolomic profiling of membrane transporters in Xe nopus laevis oocytes can be used to test their substrate specificity and role in intracellular signaling pathways.
15 citations
References
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TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
51,099 citations
8,245 citations
TL;DR: An updated protocol for Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants for a user's protein sequence.
Abstract: Phyre2 is a web-based tool for predicting and analyzing protein structure and function. Phyre2 uses advanced remote homology detection methods to build 3D models, predict ligand binding sites, and analyze amino acid variants in a protein sequence. Phyre2 is a suite of tools available on the web to predict and analyze protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a paper in Nature Protocols. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants (e.g., nonsynonymous SNPs (nsSNPs)) for a user's protein sequence. Users are guided through results by a simple interface at a level of detail they determine. This protocol will guide users from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins that are difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2
. A typical structure prediction will be returned between 30 min and 2 h after submission.
7,941 citations
TL;DR: The authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor, and test several published SARS-CoV RBD-specific monoclonal antibodies found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs.
Abstract: The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
7,324 citations
TL;DR: It is found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells, indicating that ACE2 is a functional receptor for SARS-CoV.
Abstract: Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells Together our data indicate that ACE2 is a functional receptor for SARS-CoV
5,149 citations