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Special Issue "Membrane Proteins: Structure, Function and Motion"

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

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editor

Prof. Dr. Masoud Jelokhani-Niaraki
E-Mail Website
Guest Editor
Wilfrid Laurier University, Waterloo, Canada
Interests: biophysical chemistry of membrane proteins and membrane interacting peptides; peptide and protein ion transport; antimicrobial peptides

Special Issue Information

Dear Colleagues,

Membrane proteins are present in all cells and are essential for their homeostasis and response to environmental changes. Membrane proteins are involved in a vast variety of dynamic cellular processes such as ionic and molecular transport, electron transport, signal transduction, enzymatic reactions, and intercellular communication. Despite their relative abundance and important roles in life processes, there is considerably less structural and functional information about membrane proteins in comparison to other types of proteins. The first high-resolution structure for a membrane protein was published in 1985, and, currently, more than1000 membrane protein structures (vs. more than 150,000 structures of other protein classes) have been determined. The main two challenges in determining membrane protein structures is in optimizing experimental conditions for their extraction/purification from cell membranes and their reconstitution in cell-like membranes. In their native environments, membrane proteins interact with both membrane lipids and other (membrane) proteins. This close interaction influences their biological function, which is not easily reproducible under in vitro conditions. In addition to technical problems in isolation and purification of membrane proteins in their native conformations, there are many questions about the molecular behavior of membrane proteins that are not yet answered or are only partially answered. Some of these problems include the specific and non-specific interactions of membrane proteins with lipids and other proteins, dynamic conformational changes and oligomerization of membrane proteins, membrane protein folding, modes of action of infectious structures (such as viruses) with membrane surface and membrane proteins, and the action of membrane proteins in their complex in vivo environment. As a result of these challenging problems, membrane protein studies have become a flourishing research field in molecular biophysics. Visualizing the dynamic nature of membrane proteins and their interconnections in the cell is a key element in understanding the complex, yet efficient, molecular machinery of life.

Dr. Masoud Jelokhani-Niaraki
Guest Editor

Manuscript Submission Information

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Keywords

  • membrane protein isolation and purification
  • membrane protein structure
  • dynamic conformation
  • membrane protein folding
  • protein–lipid and protein–protein interactions
  • membrane protein oligomerization
  • membrane transport
  • signal transduction and cellular communication
  • interaction with infectious agents
  • membrane proteins in vivo

Published Papers (8 papers)

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Research

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Open AccessArticle
ANT1 Activation and Inhibition Patterns Support the Fatty Acid Cycling Mechanism for Proton Transport
Int. J. Mol. Sci. 2021, 22(5), 2490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052490 - 02 Mar 2021
Cited by 1 | Viewed by 453
Abstract
Adenine nucleotide translocase (ANT) is a well-known mitochondrial exchanger of ATP against ADP. In contrast, few studies have shown that ANT also mediates proton transport across the inner mitochondrial membrane. The results of these studies are controversial and lead to different hypotheses about [...] Read more.
Adenine nucleotide translocase (ANT) is a well-known mitochondrial exchanger of ATP against ADP. In contrast, few studies have shown that ANT also mediates proton transport across the inner mitochondrial membrane. The results of these studies are controversial and lead to different hypotheses about molecular transport mechanisms. We hypothesized that the H+-transport mediated by ANT and uncoupling proteins (UCP) has a similar regulation pattern and can be explained by the fatty acid cycling concept. The reconstitution of purified recombinant ANT1 in the planar lipid bilayers allowed us to measure the membrane current after the direct application of transmembrane potential ΔΨ, which would correspond to the mitochondrial states III and IV. Experimental results reveal that ANT1 does not contribute to a basal proton leak. Instead, it mediates H+ transport only in the presence of long-chain fatty acids (FA), as already known for UCPs. It depends on FA chain length and saturation, implying that FA’s transport is confined to the lipid-protein interface. Purine nucleotides with the preference for ATP and ADP inhibited H+ transport. Specific inhibitors of ATP/ADP transport, carboxyatractyloside or bongkrekic acid, also decreased proton transport. The H+ turnover number was calculated based on ANT1 concentration determined by fluorescence correlation spectroscopy and is equal to 14.6 ± 2.5 s−1. Molecular dynamic simulations revealed a large positively charged area at the protein/lipid interface that might facilitate FA anion’s transport across the membrane. ANT’s dual function—ADP/ATP and H+ transport in the presence of FA—may be important for the regulation of mitochondrial membrane potential and thus for potential-dependent processes in mitochondria. Moreover, the expansion of proton-transport modulating drug targets to ANT1 may improve the therapy of obesity, cancer, steatosis, cardiovascular and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Open AccessArticle
A Mechanistic Model of NMDA and AMPA Receptor-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach
Int. J. Mol. Sci. 2021, 22(4), 1536; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041536 - 03 Feb 2021
Viewed by 624
Abstract
Inside hippocampal circuits, neuroplasticity events that individual cells may undergo during synaptic transmissions occur in the form of Long-Term Potentiation (LTP) and Long-Term Depression (LTD). The high density of NMDA receptors expressed on the surface of the dendritic CA1 spines confers to hippocampal [...] Read more.
Inside hippocampal circuits, neuroplasticity events that individual cells may undergo during synaptic transmissions occur in the form of Long-Term Potentiation (LTP) and Long-Term Depression (LTD). The high density of NMDA receptors expressed on the surface of the dendritic CA1 spines confers to hippocampal CA3-CA1 synapses the ability to easily undergo NMDA-mediated LTP and LTD, which is essential for some forms of explicit learning in mammals. Providing a comprehensive kinetic model that can be used for running computer simulations of the synaptic transmission process is currently a major challenge. Here, we propose a compartmentalized kinetic model for CA3-CA1 synaptic transmission. Our major goal was to tune our model in order to predict the functional impact caused by disease associated variants of NMDA receptors related to severe cognitive impairment. Indeed, for variants Glu413Gly and Cys461Phe, our model predicts negative shifts in the glutamate affinity and changes in the kinetic behavior, consistent with experimental data. These results point to the predictive power of this multiscale viewpoint, which aims to integrate the quantitative kinetic description of large interaction networks typical of system biology approaches with a focus on the quality of a few, key, molecular interactions typical of structural biology ones. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Open AccessArticle
Molecular Dynamics Simulations of Mitochondrial Uncoupling Protein 2
Int. J. Mol. Sci. 2021, 22(3), 1214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031214 - 26 Jan 2021
Viewed by 797
Abstract
Molecular dynamics (MD) simulations of uncoupling proteins (UCP), a class of transmembrane proteins relevant for proton transport across inner mitochondrial membranes, represent a complicated task due to the lack of available structural data. In this work, we use a combination of homology modelling [...] Read more.
Molecular dynamics (MD) simulations of uncoupling proteins (UCP), a class of transmembrane proteins relevant for proton transport across inner mitochondrial membranes, represent a complicated task due to the lack of available structural data. In this work, we use a combination of homology modelling and subsequent microsecond molecular dynamics simulations of UCP2 in the DOPC phospholipid bilayer, starting from the structure of the mitochondrial ATP/ADP carrier (ANT) as a template. We show that this protocol leads to a structure that is impermeable to water, in contrast to MD simulations of UCP2 structures based on the experimental NMR structure. We also show that ATP binding in the UCP2 cavity is tight in the homology modelled structure of UCP2 in agreement with experimental observations. Finally, we corroborate our results with conductance measurements in model membranes, which further suggest that the UCP2 structure modeled from ANT protein possesses additional key functional elements, such as a fatty acid-binding site at the R60 region of the protein, directly related to the proton transport mechanism across inner mitochondrial membranes. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Open AccessArticle
Tetraoctylammonium, a Long Chain Quaternary Ammonium Blocker, Promotes a Noncollapsed, Resting-Like Inactivated State in KcsA
Int. J. Mol. Sci. 2021, 22(2), 490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020490 - 06 Jan 2021
Viewed by 370
Abstract
Alkylammonium salts have been used extensively to study the structure and function of potassium channels. Here, we use the hydrophobic tetraoctylammonium (TOA+) to shed light on the structure of the inactivated state of KcsA, a tetrameric prokaryotic potassium channel that serves [...] Read more.
Alkylammonium salts have been used extensively to study the structure and function of potassium channels. Here, we use the hydrophobic tetraoctylammonium (TOA+) to shed light on the structure of the inactivated state of KcsA, a tetrameric prokaryotic potassium channel that serves as a model to its homologous eukaryotic counterparts. By the combined use of a thermal denaturation assay and the analysis of homo-Förster resonance energy transfer in a mutant channel containing a single tryptophan (W67) per subunit, we found that TOA+ binds the channel cavity with high affinity, either with the inner gate open or closed. Moreover, TOA+ bound at the cavity allosterically shifts the equilibrium of the channel’s selectivity filter conformation from conductive to an inactivated-like form. The inactivated TOA+–KcsA complex exhibits a loss in the affinity towards permeant K+ at pH 7.0, when the channel is in its closed state, but maintains the two sets of K+ binding sites and the W67–W67 intersubunit distances characteristic of the selectivity filter in the channel resting state. Thus, the TOA+–bound state differs clearly from the collapsed channel state described by X-ray crystallography and claimed to represent the inactivated form of KcsA. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Open AccessArticle
Effect of Amyloid-β Monomers on Lipid Membrane Mechanical Parameters–Potential Implications for Mechanically Driven Neurodegeneration in Alzheimer’s Disease
Int. J. Mol. Sci. 2021, 22(1), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010018 - 22 Dec 2020
Viewed by 536
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease that results in memory loss and the impairment of cognitive skills. Several mechanisms of AD’s pathogenesis were proposed, such as the progressive accumulation of amyloid-β (Aβ) and τ pathology. Nevertheless, the exact neurodegenerative mechanism of the [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disease that results in memory loss and the impairment of cognitive skills. Several mechanisms of AD’s pathogenesis were proposed, such as the progressive accumulation of amyloid-β (Aβ) and τ pathology. Nevertheless, the exact neurodegenerative mechanism of the Aβ remains complex and not fully understood. This paper proposes an alternative hypothesis of the mechanism based on maintaining the neuron membrane’s mechanical balance. The incorporation of Aβ decreases the lipid membrane’s elastic properties, which eventually leads to the impairment of membrane clustering, disruption of mechanical wave propagation, and change in gamma oscillations. The first two disrupt the neuron’s ability to function correctly while the last one decreases sensory encoding and perception enabling. To begin discussing this mechanical-balance hypothesis, we measured the effect of two selected peptides, Aβ-40 and Aβ-42, as well as their fluorescently labeled modification, on membrane mechanical properties. The decrease of bending rigidity, consistent for all investigated peptides, was observed using molecular dynamic studies and experimental flicker-noise techniques. Additionally, wave propagation was investigated with molecular dynamic studies in membranes with and without incorporated neurodegenerative peptides. A change in membrane behavior was observed in the membrane system with incorporated Aβ. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Open AccessArticle
Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria
Int. J. Mol. Sci. 2020, 21(19), 7009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197009 - 23 Sep 2020
Viewed by 567
Abstract
Resistance to antimalarial drugs has spread rapidly over the past few decades. The WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated malaria, but unfortunately these approaches are losing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance was [...] Read more.
Resistance to antimalarial drugs has spread rapidly over the past few decades. The WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated malaria, but unfortunately these approaches are losing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance was confirmed in 5 countries of the Greater Mekong subregion. We focused our study on Syk inhibitors as antimalarial drugs. The Syk protein is present in human erythrocytes, and the membrane of protein band 3 is its major target following activation by oxidant stress. Tyr phosphorylation of band 3 occurs during P. falciparum growth, leading to the release of microparticles containing hemicromes and structural weakening of the host cell membrane, simplifying merozoite reinfection. Syk inhibitors block these events by interacting with the Syk protein’s catalytic site. We performed in vitro proteomics and in silico studies and compared the results. In vitro studies were based on treatment of the parasite’s cellular cultures with different concentrations of Syk inhibitors, while proteomics studies were focused on the Tyr phosphorylation of band 3 by Syk protein with the same concentrations of drugs. In silico studies were based on different molecular modeling approaches in order to analyze and optimize the ligand–protein interactions and obtain the highest efficacy in vitro. In the presence of Syk inhibitors, we observed a marked decrease of band 3 Tyr phosphorylation according to the increase of the drug’s concentration. Our studies could be useful for the structural optimization of these compounds and for the design of novel Syk inhibitors in the future. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Review

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Open AccessReview
The SARS-Coronavirus Infection Cycle: A Survey of Viral Membrane Proteins, Their Functional Interactions and Pathogenesis
Int. J. Mol. Sci. 2021, 22(3), 1308; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031308 - 28 Jan 2021
Cited by 3 | Viewed by 1565
Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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Open AccessReview
Fake It ‘Till You Make It—The Pursuit of Suitable Membrane Mimetics for Membrane Protein Biophysics
Int. J. Mol. Sci. 2021, 22(1), 50; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010050 - 23 Dec 2020
Cited by 1 | Viewed by 861
Abstract
Membrane proteins evolved to reside in the hydrophobic lipid bilayers of cellular membranes. Therefore, membrane proteins bridge the different aqueous compartments separated by the membrane, and furthermore, dynamically interact with their surrounding lipid environment. The latter not only stabilizes membrane proteins, but directly [...] Read more.
Membrane proteins evolved to reside in the hydrophobic lipid bilayers of cellular membranes. Therefore, membrane proteins bridge the different aqueous compartments separated by the membrane, and furthermore, dynamically interact with their surrounding lipid environment. The latter not only stabilizes membrane proteins, but directly impacts their folding, structure and function. In order to be characterized with biophysical and structural biological methods, membrane proteins are typically extracted and subsequently purified from their native lipid environment. This approach requires that lipid membranes are replaced by suitable surrogates, which ideally closely mimic the native bilayer, in order to maintain the membrane proteins structural and functional integrity. In this review, we survey the currently available membrane mimetic environments ranging from detergent micelles to bicelles, nanodiscs, lipidic-cubic phase (LCP), liposomes, and polymersomes. We discuss their respective advantages and disadvantages as well as their suitability for downstream biophysical and structural characterization. Finally, we take a look at ongoing methodological developments, which aim for direct in-situ characterization of membrane proteins within native membranes instead of relying on membrane mimetics. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function and Motion)
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