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New Advancement in Membrane Transport Proteins
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New Advancement in Membrane Transport Proteins

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (18 April 2023) | Viewed by 8872

Special Issue Editor

Prof. Dr. Etana Padan

E-Mail Website
Guest Editor
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel
Interests: membrane transport system; membrane transport proteins; cryoEM; structure/function; transporter defect; human pathology

Special Issue Information

Dear Colleagues,

Membrane transport systems including the solute carriers (SLC) are a key element for cell life since they regulated the flux of nutrients, metabolites, ions, neurotransmitters, toxic compounds and drugs through cell and organelles membranes. Among membrane proteins (26% of the human genome), transporters, account for 10 %. Derangements or malfunctioning of membrane transport systems can cause a wide range of diseases. 

Thus, many represent attractive drug targets. In spite of their importance, the structure and function of many of these proteins are still unknown because they are very hydrophobic and usually are present in low amounts in the membrane. In recent years single particle cryoEM revolutionized structure determination of membrane transport proteins. However, the study of a transporter structure is far from its completion because structural dynamics, structure/function characterization and site-specific mutagenesis are required to understand the molecular mechanism and find the link of transporter defects with human pathology. In addition, high-throughput screening technologies for identification and over expression of membrane transport proteins are required to their study in vivo and in vitro.

Prof. Dr. Etana Padan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • membrane transport system
  • membrane Transport Proteins
  • cryoEM
  • structure/function
  • transporter defect
  • human pathology

Published Papers (4 papers)

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Research

26 pages, 4733 KiB  
Article
Artificial Fluorescent Glucosinolates (F-GSLs) Are Transported by the Glucosinolate Transporters GTR1/2/3
by Christa Kanstrup, Claire C. Jimidar, Josip Tomas, Giuliano Cutolo, Christoph Crocoll, Marie Schuler, Philipp Klahn, Arnaud Tatibouët and Hussam Hassan Nour-Eldin
Int. J. Mol. Sci. 2023, 24(2), 920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020920 - 04 Jan 2023
Cited by 1 | Viewed by 2431
Abstract
The glucosinolate transporters 1/2/3 (GTR1/2/3) from the Nitrate and Peptide transporter Family (NPF) play an essential role in the transport, accumulation, and distribution of the specialized plant metabolite glucosinolates. Due to representing both antinutritional and health-promoting compounds, there is increasing interest in characterizing [...] Read more.
The glucosinolate transporters 1/2/3 (GTR1/2/3) from the Nitrate and Peptide transporter Family (NPF) play an essential role in the transport, accumulation, and distribution of the specialized plant metabolite glucosinolates. Due to representing both antinutritional and health-promoting compounds, there is increasing interest in characterizing GTRs from various plant species. We generated seven artificial glucosinolates (either aliphatic or benzenic) bearing different fluorophores (Fluorescein, BODIPY, Rhodamine, Dansylamide, and NBD) and investigated the ability of GTR1/2/3 from Arabidopsis thaliana to import the fluorescent glucosinolates (F-GSLs) into oocytes from Xenopus laevis. Five out of the seven F-GSLs synthesized were imported by at least one of the GTRs. GTR1 and GTR2 were able to import three F-GSLs actively above external concentration, while GTR3 imported only one actively. Competition assays indicate that the F-GSLs are transported by the same mechanism as non-tagged natural glucosinolates. The GTR-mediated F-GSL uptake is detected via a rapid and sensitive assay only requiring simple fluorescence measurements on a standard plate reader. This is highly useful in investigations of glucosinolate transport function and provides a critical prerequisite for elucidating the relationship between structure and function through high-throughput screening of GTR mutant libraries. The F-GSL themselves may also be suitable for future studies on glucosinolate transport in vivo. Full article
(This article belongs to the Special Issue New Advancement in Membrane Transport Proteins)
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19 pages, 2891 KiB  
Article
Cross-Linking and Functional Analyses for Dimerization of a Cysteine Mutant of Glycine Transporter 1
by Jingru Wang, Hanhe Liu and Yuan-Wei Zhang
Int. J. Mol. Sci. 2022, 23(24), 16157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416157 - 18 Dec 2022
Cited by 1 | Viewed by 1673
Abstract
Glycine transporter 1 (GlyT1) is responsible for the reuptake of glycine, which regulates glutamate signaling as a co-agonist with N-methyl-D-aspartic acid (NMDA) receptors in the excitatory synapse and has been proposed to be a potential target in the development of therapies for a [...] Read more.
Glycine transporter 1 (GlyT1) is responsible for the reuptake of glycine, which regulates glutamate signaling as a co-agonist with N-methyl-D-aspartic acid (NMDA) receptors in the excitatory synapse and has been proposed to be a potential target in the development of therapies for a broad range of disorders of the central nervous system. Despite significant progress in characterizing structure and transport mechanism of the transporter, the regulation of transport function through oligomerization remains to be understood. In the present work, association of two forms of GlyT1 into dimers and higher order oligomers was detected by coimmunoprecipitation. To investigate functional properties of dimers of a GlyT1 cysteine mutant L288C, we performed oxidative cross-linking of the positioned cysteine residues in extracellular loop 3 (EL3) near the extracellular end of TM6. By analyzing the effect of copper phenanthroline (CuP)-induced dimerization on transport function, cross-linking of L288C was found to inhibit transport activity. In addition, an intramolecular ion pair Lys286-Glu289 was revealed to be critical for stabilizing EL3 in a conformation that modulates CuP-induced dimerization and transport function of the GlyT1 L288C mutant. Furthermore, the influence of transporter conformation on GlyT1 L288C dimerization was investigated. The substrate glycine, in the presence of both Na+ and Cl−, significantly reduced oxidative cross-linking, suggesting a large-scale rotation of the bundle domain during substrate transport impairs interfacial interactions between L288C protomers. The present study provides new insights into structural and functional elements regulating GlyT1 transport activity through its dimerization or oligomerization. Full article
(This article belongs to the Special Issue New Advancement in Membrane Transport Proteins)
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18 pages, 3405 KiB  
Article
Determining Ligand and Ion-Induced Conformational Changes in Serotonin Transporter with Its Fluorescent Substrates
by Mu Li, Qingyang Chen and Yuan-Wei Zhang
Int. J. Mol. Sci. 2022, 23(18), 10919; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810919 - 18 Sep 2022
Cited by 3 | Viewed by 1687
Abstract
Conformational changes are fundamental events in the transport mechanism. The serotonin transporter (SERT) catalyzes reuptake of the neurotransmitter serotonin after its release by serotonergic neurons and is the molecular target for antidepressant drugs and psychostimulants. Despite significant progress in characterizing the structure–function relationship [...] Read more.
Conformational changes are fundamental events in the transport mechanism. The serotonin transporter (SERT) catalyzes reuptake of the neurotransmitter serotonin after its release by serotonergic neurons and is the molecular target for antidepressant drugs and psychostimulants. Despite significant progress in characterizing the structure–function relationship of SERT, its conformational mechanism has not been fully understood. We present here a cell-based method for determining conformational changes in SERT with its fluorescent substrates by fluorescence imaging analysis. This method fluorometrically measures accessibility of strategically positioned cysteine residues in the substrate permeation pathway to calculate the rate constants of reactivity with MTS reagents in live or permeabilized cells. We validated this method by investigating ligand and ion-induced conformational changes in both the extracellular and cytoplasmic pathways of SERT. Furthermore, we applied this method for examining the influence of Cl− binding and vilazodone inhibition on SERT conformation. Our results showed that Cl− ion, in the presence of Na+, facilitates the conformational conversion from outward to inward open states, and that vilazodone binding stabilizes SERT in an outward open and inward-closed conformation. The present work provided insights into the conformational mechanism of SERT and also indicated that the cell-based fluorometric method is robust, straightforward to perform, and potentially applicable to any monoamine transporters in exploring the transport mechanism and mechanism of action of therapeutic agents for the treatment of several psychiatric disorders. Full article
(This article belongs to the Special Issue New Advancement in Membrane Transport Proteins)
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20 pages, 4864 KiB  
Article
A Drug Discovery Approach for an Effective Pain Therapy through Selective Inhibition of Nav1.7
by Gabriele A. Trombetti, Alessandra Mezzelani and Alessandro Orro
Int. J. Mol. Sci. 2022, 23(12), 6793; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126793 - 18 Jun 2022
Cited by 1 | Viewed by 2537
Abstract
Chronic pain is a widespread disorder affecting millions of people and is insufficiently addressed by current classes of analgesics due to significant long-term or high dosage side effects. A promising approach that was recently proposed involves the systemic inhibition of the voltage-gated sodium [...] Read more.
Chronic pain is a widespread disorder affecting millions of people and is insufficiently addressed by current classes of analgesics due to significant long-term or high dosage side effects. A promising approach that was recently proposed involves the systemic inhibition of the voltage-gated sodium channel Nav1.7, capable of cancelling pain perception completely. Notwithstanding numerous attempts, currently no drugs have been approved for the inhibition of Nav1.7. The task is complicated by the difficulty of creating a selective drug for Nav1.7, and avoiding binding to the many human paralogs performing fundamental physiological functions. In our work, we obtained a promising set of ligands with up to 5–40-fold selectivity and reaching 5.2 nanomolar binding affinity by employing a proper treatment of the problem and an innovative differential in silico screening procedure to discriminate for affinity and selectivity against the Nav paralogs. The absorption, distribution, metabolism, and excretion (ADME) properties of our top-scoring ligands were also evaluated, with good to excellent results. Additionally, our study revealed that the top-scoring ligand is a stereoisomer of an already-approved drug. These facts could reduce the time required to bring a new effective and selective Nav1.7 inhibitor to the market. Full article
(This article belongs to the Special Issue New Advancement in Membrane Transport Proteins)
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