Membrane Regulation of Protein Function

A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Functions".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 19463

Special Issue Editors

Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria
Interests: protein translocation; translocon; single channel electrophysiology; surface proton; protein-lipid interactions
Special Issues, Collections and Topics in MDPI journals
Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 31/4 Leninskiy Prospekt, 119071 Moscow, Russia
Interests: biophysics of cell and artificial membranes; bioelectrochemistry; physical chemistry of lipids; protein adsorption; self-assembly of complex protein structures; enveloped viruses; electroporation of lipid membranes; antimicrobial peptides; atomic force microscopy; fluorescent microscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is growing evidence that the lipid matrix of cellular membranes plays a significant role in regulating protein activity and signal transduction across the membrane. The community researching lipid–protein interaction approaches the topic from different aspects:

  • Mechanical regulation of proteins by changing elastic parameters of the lipid membrane, such as surface tension for mechanosensitive proteins;
  • Protein–lipid clustering into nanodomains due to preferred partitioning toward the liquid-ordered or liquid-disordered phase;
  • Protein clustering of water-soluble proteins triggered by interaction with a lipid membrane;
  • Regulation of protein activity by specific interaction with lipids;
  • Folding of peptides and intrinsically disordered proteins onto lipid membrane, and more.

The current issue aims to cover the progress in understanding the interplay between the protein function and state/composition of the lipid membrane.

Dr. Denis G. Knyazev
Dr. Oleg V. Batishchev
Guest Editors

Manuscript Submission Information

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Keywords

  • voltage gating
  • mechanogating
  • lipid activation of proteins
  • protein sorting by lipid domains
  • lipid-induced protein clustering
  • Intrinsically Disordered Proteins (IDP)
  • protein folding

Published Papers (10 papers)

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Research

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17 pages, 3446 KiB  
Article
Influenza A Virus M1 Protein Non-Specifically Deforms Charged Lipid Membranes and Specifically Interacts with the Raft Boundary
Membranes 2023, 13(1), 76; https://doi.org/10.3390/membranes13010076 - 07 Jan 2023
Cited by 1 | Viewed by 2967
Abstract
Topological rearrangements of biological membranes, such as fusion and fission, often require a sophisticated interplay between different proteins and cellular membranes. However, in the case of fusion proteins of enveloped viruses, even one molecule can execute membrane restructurings. Growing evidence indicates that matrix [...] Read more.
Topological rearrangements of biological membranes, such as fusion and fission, often require a sophisticated interplay between different proteins and cellular membranes. However, in the case of fusion proteins of enveloped viruses, even one molecule can execute membrane restructurings. Growing evidence indicates that matrix proteins of enveloped viruses can solely trigger the membrane bending required for another crucial step in virogenesis, the budding of progeny virions. For the case of the influenza A virus matrix protein M1, different studies report both in favor and against M1 being able to produce virus-like particles without other viral proteins. Here, we investigated the physicochemical mechanisms of M1 membrane activity on giant unilamellar vesicles of different lipid compositions using fluorescent confocal microscopy. We confirmed that M1 predominantly interacts electrostatically with the membrane, and its ability to deform the lipid bilayer is non-specific and typical for membrane-binding proteins and polypeptides. However, in the case of phase-separating membranes, M1 demonstrates a unique ability to induce macro-phase separation, probably due to the high affinity of M1’s amphipathic helices to the raft boundary. Thus, we suggest that M1 is tailored to deform charged membranes with a specific activity in the case of phase-separating membranes. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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15 pages, 2370 KiB  
Article
A Mechanism of Double-Membrane Vesicle Formation from Liquid-Ordered/Liquid-Disordered Phase Separated Spherical Membrane
Membranes 2023, 13(1), 25; https://doi.org/10.3390/membranes13010025 - 24 Dec 2022
Viewed by 1275
Abstract
Genome replication of coronaviruses takes place in specific cellular compartments, in so-called double-membrane vesicles (DMVs), formed from the endoplasmic reticulum (ER). An intensive production of DMVs is induced by non-structural viral proteins. Here, we proposed a possible mechanism of the DMV formation from [...] Read more.
Genome replication of coronaviruses takes place in specific cellular compartments, in so-called double-membrane vesicles (DMVs), formed from the endoplasmic reticulum (ER). An intensive production of DMVs is induced by non-structural viral proteins. Here, we proposed a possible mechanism of the DMV formation from ER-derived spherical vesicles where liquid-ordered and liquid-disordered lipid phases coexist. These vesicles are supposed to divide into two homogeneous liquid-ordered and liquid-disordered vesicles. The formation of two spherical vesicles constituting DMV requires a mechanical work to be performed. We considered the excess energy of the boundary between the coexisting lipid phases as the main driving force behind the division of the initial vesicle. Explicitly accounting for the energy of elastic deformations and the interphase boundary energy, we analyzed a range of physical parameters where the DMV formation is possible. We concluded that this process can principally take place in a very narrow range of system parameters. The most probable diameter of DMVs formed according to the proposed mechanism appeared to be approximately 220 nm, in an agreement with the average diameter of DMVs observed in vivo. Our consideration predicts the DMV size to be strongly limited from above. The developed analysis can be utilized for the production of DMVs in model systems. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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13 pages, 2147 KiB  
Article
Structural Role of Plasma Membrane Sterols in Osmotic Stress Tolerance of Yeast Saccharomyces cerevisiae
Membranes 2022, 12(12), 1278; https://doi.org/10.3390/membranes12121278 - 17 Dec 2022
Cited by 2 | Viewed by 1973
Abstract
Yeast S. cerevisiae has been shown to suppress a sterol biosynthesis as a response to hyperosmotic stress. In the case of sodium stress, the failure to suppress biosynthesis leads to an increase in cytosolic sodium. The major yeast sterol, ergosterol, is known to [...] Read more.
Yeast S. cerevisiae has been shown to suppress a sterol biosynthesis as a response to hyperosmotic stress. In the case of sodium stress, the failure to suppress biosynthesis leads to an increase in cytosolic sodium. The major yeast sterol, ergosterol, is known to regulate functioning of plasma membrane proteins. Therefore, it has been suggested that the suppression of its biosynthesis is needed to adjust the activity of the plasma membrane sodium pumps and channels. However, as the sterol concentration is in the range of thirty to forty percent of total plasma membrane lipids, it is believed that its primary biological role is not regulatory but structural. Here we studied how lowering the sterol content affects the response of a lipid bilayer to an osmotic stress. In accordance with previous observations, we found that a decrease of the sterol fraction increases a water permeability of the liposomal membranes. Yet, we also found that sterol-free giant unilamellar vesicles reduced their volume during transient application of the hyperosmotic stress to a greater extent than the sterol-rich ones. Furthermore, our data suggest that lowering the sterol content in yeast cells allows the shrinkage to prevent the osmotic pressure-induced plasma membrane rupture. We also found that mutant yeast cells with the elevated level of sterol accumulated propidium iodide when exposed to mild hyperosmotic conditions followed by hypoosmotic stress. It is likely that the decrease in a plasma membrane sterol content stimulates a drop in cell volume under hyperosmotic stress, which is beneficial in the case of a subsequent hypo-osmotic one. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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13 pages, 1234 KiB  
Article
X-ray Reflectivity Study of Polylysine Adsorption on the Surface of DMPS Monolayers
Membranes 2022, 12(12), 1223; https://doi.org/10.3390/membranes12121223 - 02 Dec 2022
Cited by 1 | Viewed by 1284
Abstract
The results of a systematic study on the adsorption of polylysine molecules of different lengths on the surface of a 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) monolayer in the liquid (LE) and condensed (LC) states are presented. A compressibility diagram and the Volta potential were [...] Read more.
The results of a systematic study on the adsorption of polylysine molecules of different lengths on the surface of a 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) monolayer in the liquid (LE) and condensed (LC) states are presented. A compressibility diagram and the Volta potential were recorded with the Langmuir monolayer technique and further analyzed with the empirical approach. The structure of the monolayer films with adsorbed polypeptides was studied with synchrotron X-ray reflectometry. Two- and three-layer slab models describe the reflectivity data fairly well and reveal both the significant structural changes and the dehydration of the polar groups induced by all polylysines used at the maximal coverage of the monolayer interface in both the LE and LC states. On the one hand, in the LE phase of the monolayer (area per molecule A ≅ 70 Ǻ2), the integrated electron density of the lipid headgroup region is approximately half the density contained in the clean monolayer. This indicates both significant compaction and dehydration in the polar groups of the lipids, caused by the adsorption of polypeptides. On the other hand, in the LC state (A ≅ 40 Ǻ2), the degree of the hydration of the polar region is similar to that for the initial DMPS monolayer. However, both the electron density and the thickness of the head group region differ significantly from the values of these parameters for the clean monolayer in the LC state. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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19 pages, 3557 KiB  
Article
Spectroscopy Study of Albumin Interaction with Negatively Charged Liposome Membranes: Mutual Structural Effects of the Protein and the Bilayers
Membranes 2022, 12(11), 1031; https://doi.org/10.3390/membranes12111031 - 23 Oct 2022
Cited by 1 | Viewed by 1414
Abstract
Liposomes as drug carriers are usually injected into the systemic circulation where they are instantly exposed to plasma proteins. Liposome–protein interactions can affect both the stability of liposomes and the conformation of the associated protein leading to the altered biodistribution of the carrier. [...] Read more.
Liposomes as drug carriers are usually injected into the systemic circulation where they are instantly exposed to plasma proteins. Liposome–protein interactions can affect both the stability of liposomes and the conformation of the associated protein leading to the altered biodistribution of the carrier. In this work, mutual effects of albumin and liposomal membrane in the course of the protein’s adsorption were examined in terms of quantity of bound protein, its structure, liposome membrane permeability, and changes in physicochemical characteristics of the liposomes. Fluorescence spectroscopy methods and Fourier transform infrared spectroscopy (ATR-FTIR), which provides information about specific groups in lipids involved in interaction with the protein, were used to monitor adsorption of albumin with liposomes based on egg phosphatidylcholine with various additives of negatively charged lipidic components, such as phosphatidylinositol, ganglioside GM1, or the acidic lipopeptide. Less than a dozen of the protein molecules were tightly bound to a liposome independently of bilayer composition, yet they had a detectable impact on the bilayer. Albumin conformational changes during adsorption were partially related to bilayer microhydrophobicity. Ganglioside GM1 showed preferable features for evading undesirable structural changes. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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16 pages, 2580 KiB  
Article
A Model of Lipid Monolayer–Bilayer Fusion of Lipid Droplets and Peroxisomes
Membranes 2022, 12(10), 992; https://doi.org/10.3390/membranes12100992 - 13 Oct 2022
Cited by 2 | Viewed by 1331
Abstract
Lipid droplets are unique organelles that store neutral lipids encapsulated by the lipid monolayer. In some processes of cellular metabolism, lipid droplets interact with peroxisomes resulting in the fusion of their envelopes and the formation of protrusions of the peroxisome monolayer, called pexopodia. [...] Read more.
Lipid droplets are unique organelles that store neutral lipids encapsulated by the lipid monolayer. In some processes of cellular metabolism, lipid droplets interact with peroxisomes resulting in the fusion of their envelopes and the formation of protrusions of the peroxisome monolayer, called pexopodia. The formation of pexopodia is facilitated by free fatty acids generated during lipolysis within lipid droplets. In this work, we studied the fusion of monolayer and bilayer membranes during the interaction between lipid droplets and peroxisomes. To this end, we built the energy trajectory of this process using the continuum elasticity theory and investigated the molecular details of the fusion structures utilizing molecular dynamics. We divided the fusion process into two stages: formation of a stalk and its consequent expansion into pexopodia. We found that in the considered system, the stalk was energetically more stable and had a lower energy barrier of formation compared to the case of bilayer fusion. The further evolution of the stalk depended on the value of the spontaneous curvature of the membrane in a threshold manner. We attributed the possible expansion of the stalk to the incorporation of free fatty acids into the stalk region. The developed model allowed describing quantitatively the process of monolayer–bilayer fusion. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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16 pages, 2428 KiB  
Article
Hydrophobic Mismatch Controls the Mode of Membrane-Mediated Interactions of Transmembrane Peptides
Membranes 2022, 12(1), 89; https://doi.org/10.3390/membranes12010089 - 13 Jan 2022
Cited by 9 | Viewed by 1708
Abstract
Various cellular processes require the concerted cooperative action of proteins. The possibility for such synchronization implies the occurrence of specific long-range interactions between the involved protein participants. Bilayer lipid membranes can mediate protein–protein interactions via relatively long-range elastic deformations induced by the incorporated [...] Read more.
Various cellular processes require the concerted cooperative action of proteins. The possibility for such synchronization implies the occurrence of specific long-range interactions between the involved protein participants. Bilayer lipid membranes can mediate protein–protein interactions via relatively long-range elastic deformations induced by the incorporated proteins. We considered the interactions between transmembrane peptides mediated by elastic deformations using the framework of the theory of elasticity of lipid membranes. An effective peptide shape was assumed to be cylindrical, hourglass-like, or barrel-like. The interaction potentials were obtained for membranes of different thicknesses and elastic rigidities. Cylindrically shaped peptides manifest almost neutral average interactions—they attract each other at short distances and repel at large ones, independently of membrane thickness or rigidity. The hourglass-like peptides repel each other in thin bilayers and strongly attract each other in thicker bilayers. On the contrary, the barrel-like peptides repel each other in thick bilayers and attract each other in thinner membranes. These results potentially provide possible mechanisms of control for the mode of protein–protein interactions in membrane domains with different bilayer thicknesses. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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13 pages, 1571 KiB  
Article
Amphipathic Peptides Impede Lipid Domain Fusion in Phase-Separated Membranes
Membranes 2021, 11(11), 797; https://doi.org/10.3390/membranes11110797 - 20 Oct 2021
Cited by 10 | Viewed by 1903
Abstract
Cell membranes are heterogeneous in lipid composition which leads to the phase separation with the formation of nanoscopic liquid-ordered domains, also called rafts. There are multiple cell processes whereby the clustering of these domains into a larger one might be involved, which is [...] Read more.
Cell membranes are heterogeneous in lipid composition which leads to the phase separation with the formation of nanoscopic liquid-ordered domains, also called rafts. There are multiple cell processes whereby the clustering of these domains into a larger one might be involved, which is responsible for such important processes as signal transduction, polarized sorting, or immune response. Currently, antimicrobial amphipathic peptides are considered promising antimicrobial, antiviral, and anticancer therapeutic agents. Here, within the framework of the classical theory of elasticity adapted for lipid membranes, we investigate how the presence of the peptides in a phase-separated membrane influences the fusion of the domains. We show that the peptides tend to occupy the boundaries of liquid-ordered domains and significantly increase the energy barrier of the domain-domain fusion, which might lead to misregulation of raft clustering and adverse consequences for normal cell processes. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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15 pages, 2371 KiB  
Article
The Cytoplasmic Tail of Influenza A Virus Hemagglutinin and Membrane Lipid Composition Change the Mode of M1 Protein Association with the Lipid Bilayer
Membranes 2021, 11(10), 772; https://doi.org/10.3390/membranes11100772 - 10 Oct 2021
Cited by 7 | Viewed by 2692
Abstract
Influenza A virus envelope contains lipid molecules of the host cell and three integral viral proteins: major hemagglutinin, neuraminidase, and minor M2 protein. Membrane-associated M1 matrix protein is thought to interact with the lipid bilayer and cytoplasmic domains of integral viral proteins to [...] Read more.
Influenza A virus envelope contains lipid molecules of the host cell and three integral viral proteins: major hemagglutinin, neuraminidase, and minor M2 protein. Membrane-associated M1 matrix protein is thought to interact with the lipid bilayer and cytoplasmic domains of integral viral proteins to form infectious virus progeny. We used small-angle X-ray scattering (SAXS) and complementary techniques to analyze the interactions of different components of the viral envelope with M1 matrix protein. Small unilamellar liposomes composed of various mixtures of synthetic or “native” lipids extracted from Influenza A/Puerto Rico/8/34 (H1N1) virions as well as proteoliposomes built from the viral lipids and anchored peptides of integral viral proteins (mainly, hemagglutinin) were incubated with isolated M1 and measured using SAXS. The results imply that M1 interaction with phosphatidylserine leads to condensation of the lipid in the protein-contacting monolayer, thus resulting in formation of lipid tubules. This effect vanishes in the presence of the liquid-ordered (raft-forming) constituents (sphingomyelin and cholesterol) regardless of their proportion in the lipid bilayer. We also detected a specific role of the hemagglutinin anchoring peptides in ordering of viral lipid membrane into the raft-like one. These peptides stimulate the oligomerization of M1 on the membrane to form a viral scaffold for subsequent budding of the virion from the plasma membrane of the infected cell. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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Review

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33 pages, 1288 KiB  
Review
Determination of Elastic Parameters of Lipid Membranes with Molecular Dynamics: A Review of Approaches and Theoretical Aspects
Membranes 2022, 12(11), 1149; https://doi.org/10.3390/membranes12111149 - 16 Nov 2022
Cited by 8 | Viewed by 1907
Abstract
Lipid membranes are abundant in living organisms, where they constitute a surrounding shell for cells and their organelles. There are many circumstances in which the deformations of lipid membranes are involved in living cells: fusion and fission, membrane-mediated interaction between membrane inclusions, lipid–protein [...] Read more.
Lipid membranes are abundant in living organisms, where they constitute a surrounding shell for cells and their organelles. There are many circumstances in which the deformations of lipid membranes are involved in living cells: fusion and fission, membrane-mediated interaction between membrane inclusions, lipid–protein interaction, formation of pores, etc. In all of these cases, elastic parameters of lipid membranes are important for the description of membrane deformations, as these parameters determine energy barriers and characteristic times of membrane-involved phenomena. Since the development of molecular dynamics (MD), a variety of in silico methods have been proposed for the determination of elastic parameters of simulated lipid membranes. These MD methods allow for the consideration of details unattainable in experimental techniques and represent a distinct scientific field, which is rapidly developing. This work provides a review of these MD approaches with a focus on theoretical aspects. Two main challenges are identified: (i) the ambiguity in the transition from the continuum description of elastic theories to the discrete representation of MD simulations, and (ii) the determination of intrinsic elastic parameters of lipid mixtures, which is complicated due to the composition–curvature coupling effect. Full article
(This article belongs to the Special Issue Membrane Regulation of Protein Function)
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