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Special Issue "Lipid-Protein and Protein-Protein Interactions in Membranes"

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 (29 February 2020).

Special Issue Editors

Prof. Dr. José Manuel González Ros
E-Mail Website
Guest Editor
Instituto de Biología Molecular y Celular Universidad Miguel Hernández de Elche Edificio Torregaitán, Elche, Alicante, Spain
Interests: structure/function relationships in membrane proteins: neuroreceptors and ion channels; lipid–protein and protein–protein interactions in biological membranes; potential applications to drug discovery
Prof. Dr. Jose Antonio Poveda Larrosa
E-Mail Website
Co-Guest Editor
Inst Invest Desarrollo & Innovac Biotecnol Sanita, Universidad Miguel Hernandez de Elche, E-03202 Alicante, Spain
Interests: structure–function relationship in membrane proteins; lipid–protein interactions; modulation of ion channel structure and function

Special Issue Information

Dear Colleagues,

The application of finer experimental and computational techniques is providing increasing evidence that the structure and function of many membrane proteins are modulated by the surrounding membrane lipids. The mechanisms behind such modulation are diverse and highly complex. For instance, lipid modulation may be exerted directly, through binding of specific lipids to defined binding sites on the membrane protein surface. Alternatively, membrane lipids may segregate domains within the membrane, into which certain proteins partition preferentially or even exclusively and have the chance to find different interacting partners and thus modify their function. The latter is a dynamic process in which changes in lipid composition, such as those found in response to drug treatments or between quiescent and proliferating cellular states, cause a reorganization of membrane domains, a redistribution of membrane proteins, and a drastic change in cellular responses. This makes cellular membranes key players in cell physiology and important pharmacological targets, as there are hundreds of different integral and peripheral membrane proteins involved in the propagation of signals that regulate cell metabolism, proliferation, differentiation or death.

In an attempt to bring together recent advances in this field, José A. Poveda and I will co-edit a Special Issue in the International Journal of Molecular Sciences (IF:4.183) on the topic “Lipid–Protein and Protein–Protein Interactions in Membranes”. We will be delighted if we could have your contribution to this exciting project.

Prof. José Manuel González Ros
Prof. Jose Antonio Poveda Larrosa
Guest Editors

Manuscript Submission Information

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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.

Published Papers (12 papers)

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Research

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Article
Lipid Composition Affects the Efficiency in the Functional Reconstitution of the Cytochrome c Oxidase
Int. J. Mol. Sci. 2020, 21(19), 6981; https://doi.org/10.3390/ijms21196981 - 23 Sep 2020
Cited by 1 | Viewed by 650
Abstract
The transmembrane protein cytochrome c oxidase (CcO) is the terminal oxidase in the respiratory chain of many aerobic organisms and catalyzes the reduction of dioxygen to water. This process maintains an electrochemical proton gradient across the membrane hosting the oxidase. C [...] Read more.
The transmembrane protein cytochrome c oxidase (CcO) is the terminal oxidase in the respiratory chain of many aerobic organisms and catalyzes the reduction of dioxygen to water. This process maintains an electrochemical proton gradient across the membrane hosting the oxidase. CcO is a well-established model enzyme in bioenergetics to study the proton-coupled electron transfer reactions and protonation dynamics involved in these processes. Its catalytic mechanism is subject to ongoing intense research. Previous research, however, was mainly focused on the turnover of oxygen and electrons in CcO, while studies reporting proton turnover rates of CcO, that is the rate of proton uptake by the enzyme, are scarce. Here, we reconstitute CcO from R. sphaeroides into liposomes containing a pH sensitive dye and probe changes of the pH value inside single proteoliposomes using fluorescence microscopy. CcO proton turnover rates are quantified at the single-enzyme level. In addition, we recorded the distribution of the number of functionally reconstituted CcOs across the proteoliposome population. Studies are performed using proteoliposomes made of native lipid sources, such as a crude extract of soybean lipids and the polar lipid extract of E. coli, as well as purified lipid fractions, such as phosphatidylcholine extracted from soybean lipids. It is shown that these lipid compositions have only minor effects on the CcO proton turnover rate, but can have a strong impact on the reconstitution efficiency of functionally active CcOs. In particular, our experiments indicate that efficient functional reconstitution of CcO is strongly promoted by the addition of anionic lipids like phosphatidylglycerol and cardiolipin. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Article
Patches and Blebs: A Comparative Study of the Composition and Biophysical Properties of Two Plasma Membrane Preparations from CHO Cells
Int. J. Mol. Sci. 2020, 21(7), 2643; https://doi.org/10.3390/ijms21072643 - 10 Apr 2020
Cited by 2 | Viewed by 861
Abstract
This study was aimed at preparing and characterizing plasma membranes (PM) from Chinese Hamster Ovary (CHO) cells. Two methods of PM preparation were applied, one based on adhering cells to a poly-lysine-coated surface, followed by hypotonic lysis and removal of intracellular components, so [...] Read more.
This study was aimed at preparing and characterizing plasma membranes (PM) from Chinese Hamster Ovary (CHO) cells. Two methods of PM preparation were applied, one based on adhering cells to a poly-lysine-coated surface, followed by hypotonic lysis and removal of intracellular components, so that PM patches remain adhered to each other, and a second one consisting of bleb induction in cells, followed by separation of giant plasma membrane vesicles (GPMV). Both methods gave rise to PM in sufficient amounts to allow biophysical and biochemical characterization. Laurdan generalized polarization was used to measure molecular order in membranes, PM preparations were clearly more ordered than the average cell membranes (GP ≈0.450 vs. ≈0.20 respectively). Atomic force microscopy was used in the force spectroscopy mode to measure breakthrough forces of PM, both PM preparations provided values in the 4–6 nN range, while the corresponding value for whole cell lipid extracts was ≈2 nN. Lipidomic analysis of the PM preparations revealed that, as compared to the average cell membranes, PM were enriched in phospholipids containing 30–32 C atoms in their acyl chains but were relatively poor in those containing 34–40 C atoms. PM contained more saturated and less polyunsaturated fatty acids than the average cell membranes. Blebs (GPMV) and patches were very similar in their lipid composition, except that blebs contained four-fold the amount of cholesterol of patches (≈23 vs. ≈6 mol% total membrane lipids) while the average cell lipids contained 3 mol%. The differences in lipid composition are in agreement with the observed variations in physical properties between PM and whole cell membranes. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Article
The Binding of Aβ42 Peptide Monomers to Sphingomyelin/Cholesterol/Ganglioside Bilayers Assayed by Density Gradient Ultracentrifugation
Int. J. Mol. Sci. 2020, 21(5), 1674; https://doi.org/10.3390/ijms21051674 - 29 Feb 2020
Cited by 4 | Viewed by 687
Abstract
The binding of Aβ42 peptide monomers to sphingomyelin/cholesterol (1:1 mol ratio) bilayers containing 5 mol% gangliosides (either GM1, or GT1b, or a mixture of brain gangliosides) has been assayed by density gradient ultracentrifugation. This procedure provides a direct method for measuring vesicle-bound peptides [...] Read more.
The binding of Aβ42 peptide monomers to sphingomyelin/cholesterol (1:1 mol ratio) bilayers containing 5 mol% gangliosides (either GM1, or GT1b, or a mixture of brain gangliosides) has been assayed by density gradient ultracentrifugation. This procedure provides a direct method for measuring vesicle-bound peptides after non-bound fraction separation. This centrifugation technique has rarely been used in this context previously. The results show that gangliosides increase by about two-fold the amount of Aβ42 bound to sphingomyelin/cholesterol vesicles. Complementary studies of the same systems using thioflavin T fluorescence, Langmuir monolayers or infrared spectroscopy confirm the ganglioside-dependent increased binding. Furthermore these studies reveal that gangliosides facilitate the aggregation of Aβ42 giving rise to more extended β-sheets. Thus, gangliosides have both a quantitative and a qualitative effect on the binding of Aβ42 to sphingomyelin/cholesterol bilayers. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Article
The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells
Int. J. Mol. Sci. 2020, 21(3), 941; https://doi.org/10.3390/ijms21030941 - 31 Jan 2020
Cited by 2 | Viewed by 859
Abstract
Brain aging involves changes in the lipid membrane composition that lead to a decrease in membrane excitability and neurotransmitter release. These membrane modifications have been identified as contributing factors in age-related memory decline. In this sense, precursors of phospholipids (PLs) can restore the [...] Read more.
Brain aging involves changes in the lipid membrane composition that lead to a decrease in membrane excitability and neurotransmitter release. These membrane modifications have been identified as contributing factors in age-related memory decline. In this sense, precursors of phospholipids (PLs) can restore the physiological composition of cellular membranes and produce valuable therapeutic effects in brain aging. Among promising drugs, alpha-glycerylphosphorylethanolamine (GPE) has demonstrated protective effects in amyloid-injured astrocytes and in an aging model of human neural stem cells. However, the compound properties on mature neuronal cells remain unexplored. Herein, GPE was tested in human hippocampal neurons, which are involved in learning and memory, and characterized by a functional cholinergic transmission, thus representing a valuable cellular model to explore the beneficial properties of GPE. GPE induced the release of the main membrane phospholipids and of the acetylcholine neurotransmitter. Moreover, the compound reduced lipid peroxidation and enhanced membrane fluidity of human brain cells. GPE counteracted the DNA damage and viability decrease observed in in vitro aged neurons. Among GPE treatment effects, the autophagy was found positively upregulated. Overall, these results confirm the beneficial effects of GPE treatment and suggest the compound as a promising drug to preserve hippocampal neurons and virtually memory performances. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Article
Hepatitis C Virus p7 Induces Membrane Permeabilization by Interacting with Phosphatidylserine
Int. J. Mol. Sci. 2020, 21(3), 897; https://doi.org/10.3390/ijms21030897 - 30 Jan 2020
Viewed by 905
Abstract
Hepatitis C virus (HCV) p7 is known to be a nonselective cation channel for HCV maturation. Because the interaction of HCV proteins with host lipids in the endoplasmic reticulum membrane is crucial for the budding process, the identification of p7–lipid interactions could be [...] Read more.
Hepatitis C virus (HCV) p7 is known to be a nonselective cation channel for HCV maturation. Because the interaction of HCV proteins with host lipids in the endoplasmic reticulum membrane is crucial for the budding process, the identification of p7–lipid interactions could be important for understanding the HCV life cycle. Here, we report that p7 interacts with phosphatidylserine (PS) to induce membrane permeabilization. The interaction of p7 with PS was not inhibited by Gd3+ ions, which have been known to interact with negatively charged lipids, but channel activity and p7-induced mitochondrial depolarization were inhibited by Gd3+ ions. From the present results, we suggest that the p7–PS interaction plays an essential role in regulating its ion channel function and could be a potential molecular target for anti-HCV therapy. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Article
Effects of Membrane and Biological Target on the Structural and Allosteric Properties of Recoverin: A Computational Approach
Int. J. Mol. Sci. 2019, 20(20), 5009; https://doi.org/10.3390/ijms20205009 - 10 Oct 2019
Cited by 4 | Viewed by 1022
Abstract
Recoverin (Rec) is a prototypical calcium sensor protein primarily expressed in the vertebrate retina. The binding of two Ca2+ ions to the functional EF-hand motifs induces the extrusion of a myristoyl group that increases the affinity of Rec for the membrane and [...] Read more.
Recoverin (Rec) is a prototypical calcium sensor protein primarily expressed in the vertebrate retina. The binding of two Ca2+ ions to the functional EF-hand motifs induces the extrusion of a myristoyl group that increases the affinity of Rec for the membrane and leads to the formation of a complex with rhodopsin kinase (GRK1). Here, unbiased all-atom molecular dynamics simulations were performed to monitor the spontaneous insertion of the myristoyl group into a model multicomponent biological membrane for both isolated Rec and for its complex with a peptide from the GRK1 target. It was found that the functional membrane anchoring of the myristoyl group is triggered by persistent electrostatic protein-membrane interactions. In particular, salt bridges between Arg43, Arg46 and polar heads of phosphatidylserine lipids are necessary to enhance the myristoyl hydrophobic packing in the Rec-GRK1 assembly. The long-distance communication between Ca2+-binding EF-hands and residues at the interface with GRK1 is significantly influenced by the presence of the membrane, which leads to dramatic changes in the connectivity of amino acids mediating the highest number of persistent interactions (hubs). In conclusion, specific membrane composition and allosteric interactions are both necessary for the correct assembly and dynamics of functional Rec-GRK1 complex. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Review

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Review
Steroids and TRP Channels: A Close Relationship
Int. J. Mol. Sci. 2020, 21(11), 3819; https://doi.org/10.3390/ijms21113819 - 27 May 2020
Cited by 4 | Viewed by 1179
Abstract
Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and [...] Read more.
Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others. TRP channels are finely modulated by different mechanisms: regulation of their function and/or by control of their expression or cellular/subcellular localization. These mechanisms are subject to being affected by several endogenously-produced compounds, some of which are of a lipidic nature such as steroids. Fascinatingly, steroids and TRP channels closely interplay to modulate several physiological events. Certain TRP channels are affected by the typical genomic long-term effects of steroids but others are also targets for non-genomic actions of some steroids that act as direct ligands of these receptors, as will be reviewed here. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Review
Lipid–Protein and Protein–Protein Interactions in the Pulmonary Surfactant System and Their Role in Lung Homeostasis
Int. J. Mol. Sci. 2020, 21(10), 3708; https://doi.org/10.3390/ijms21103708 - 25 May 2020
Cited by 11 | Viewed by 1591
Abstract
Pulmonary surfactant is a lipid/protein complex synthesized by the alveolar epithelium and secreted into the airspaces, where it coats and protects the large respiratory air–liquid interface. Surfactant, assembled as a complex network of membranous structures, integrates elements in charge of reducing surface tension [...] Read more.
Pulmonary surfactant is a lipid/protein complex synthesized by the alveolar epithelium and secreted into the airspaces, where it coats and protects the large respiratory air–liquid interface. Surfactant, assembled as a complex network of membranous structures, integrates elements in charge of reducing surface tension to a minimum along the breathing cycle, thus maintaining a large surface open to gas exchange and also protecting the lung and the body from the entrance of a myriad of potentially pathogenic entities. Different molecules in the surfactant establish a multivalent crosstalk with the epithelium, the immune system and the lung microbiota, constituting a crucial platform to sustain homeostasis, under health and disease. This review summarizes some of the most important molecules and interactions within lung surfactant and how multiple lipid–protein and protein–protein interactions contribute to the proper maintenance of an operative respiratory surface. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Review
Modulation of Function, Structure and Clustering of K+ Channels by Lipids: Lessons Learnt from KcsA
Int. J. Mol. Sci. 2020, 21(7), 2554; https://doi.org/10.3390/ijms21072554 - 07 Apr 2020
Cited by 4 | Viewed by 892
Abstract
KcsA, a prokaryote tetrameric potassium channel, was the first ion channel ever to be structurally solved at high resolution. This, along with the ease of its expression and purification, made KcsA an experimental system of choice to study structure–function relationships in ion channels. [...] Read more.
KcsA, a prokaryote tetrameric potassium channel, was the first ion channel ever to be structurally solved at high resolution. This, along with the ease of its expression and purification, made KcsA an experimental system of choice to study structure–function relationships in ion channels. In fact, much of our current understanding on how the different channel families operate arises from earlier KcsA information. Being an integral membrane protein, KcsA is also an excellent model to study how lipid–protein and protein–protein interactions within membranes, modulate its activity and structure. In regard to the later, a variety of equilibrium and non-equilibrium methods have been used in a truly multidisciplinary effort to study the effects of lipids on the KcsA channel. Remarkably, both experimental and “in silico” data point to the relevance of specific lipid binding to two key arginine residues. These residues are at non-annular lipid binding sites on the protein and act as a common element to trigger many of the lipid effects on this channel. Thus, processes as different as the inactivation of channel currents or the assembly of clusters from individual KcsA channels, depend upon such lipid binding. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Review
Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis
Int. J. Mol. Sci. 2020, 21(7), 2412; https://doi.org/10.3390/ijms21072412 - 31 Mar 2020
Cited by 10 | Viewed by 1278
Abstract
Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular [...] Read more.
Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular content. Therefore, these types of cell death have an inflammatory phenotype. Each type of regulated necrosis is mediated by a defined machinery comprising protein and lipid molecules. Here, we discuss how the interaction and reshaping of these cellular components are essential and distinctive processes during pyroptosis, necroptosis, and ferroptosis. We point out that although the plasma membrane is the common target in regulated necrosis, different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Current efforts are focused on new therapies that target critical protein and lipid molecules on these pathways to fight human pathologies associated with inflammation. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Review
The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy
Int. J. Mol. Sci. 2020, 21(7), 2322; https://doi.org/10.3390/ijms21072322 - 27 Mar 2020
Viewed by 1282
Abstract
The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal [...] Read more.
The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s lipid composition, regulation of the lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s lipids, an approach known as membrane-lipid therapy (MLT) or melitherapy. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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Review
Flotillins: At the Intersection of Protein S-Palmitoylation and Lipid-Mediated Signaling
Int. J. Mol. Sci. 2020, 21(7), 2283; https://doi.org/10.3390/ijms21072283 - 26 Mar 2020
Cited by 8 | Viewed by 1467
Abstract
Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, [...] Read more.
Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane–cytosol interface. Additional functions unique to flotillin-1 have been discovered recently. The membrane-binding of flotillins is regulated by S-palmitoylation and N-myristoylation, hydrophobic interactions involving specific regions of the polypeptide chain and, to some extent, also by their oligomerization. All these factors endow flotillins with an ability to associate with the sphingolipid/cholesterol-rich plasma membrane domains called rafts. In this review, we focus on the critical input of lipids to the regulation of the flotillin association with rafts and thereby to their functioning. In particular, we discuss how the recent developments in the field of protein S-palmitoylation have contributed to the understanding of flotillin1/2-mediated processes, including endocytosis, and of those dependent exclusively on flotillin-1. We also emphasize that flotillins affect directly or indirectly the cellular levels of lipids involved in diverse signaling cascades, including sphingosine-1-phosphate and PI(4,5)P2. The mutual relations between flotillins and distinct lipids are key to the regulation of their involvement in numerous cellular processes. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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