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Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes:...
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Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 12887

Special Issue Editors

Dr. Lladó Victoria

E-Mail Website
Guest Editor
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Ctra. de Valldemossa km 7.5, E-07122 Palma, Spain
Interests: lipid biomedicines; translational medicine; melitherapy; oncology; neurodegeneration; LAM561; clinical development
Prof. Dr. Garth L. Nicolson

E-Mail Website1 Website2
Guest Editor
President, Chief Scientific Officer at Institute for Molecular Medicine, Huntington Beach, CA, USA
Interests: membranes; membrane lipid replacement; lipid bilayers; Mycoplasma; cellular biology; laboratory medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

After several attempts to present a plausible model to explain the structure and functions of cell membranes, Singer and Nicolson published in 1972 a seminal paper introducing the Fluid Mosaic model of the plasma membrane to explain the dynamic organization of lipids that form a lipid bilayer and their association with membrane-interacting proteins. Fifty years after this publication, the model continues to be valid, and the new concepts introduced on membrane structure have validated the original lipid bilayer architecture with intercalated and bound proteins, extending the initial model with new aspects that highlight the richness and diversity of membrane structures, such as membrane microdomains, lipid phases, and membrane–cytoskeleton interactions, among others. The discovery of protein structure was followed by the development of therapies based on their interactions with small molecules and biologicals, and similarly, the knowledge of membrane structure and dynamics has paved the way for the development of food supplements and medicines to treat a variety of conditions that target membrane lipid metabolism or the membrane itself.

The scope of this issue is to describe important aspects of membrane structure in relation to its cellular functions, pathological alterations and the development of biomedicines and supplements from the basic knowledge assembled during the 50 years after the publication of the Fluid Mosaic model.

Dr. Lladó Victoria
Prof. Dr. Garth L. Nicolson
Guest Editors

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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • lipid structure
  • membrane structure
  • lipid biomedicines
  • membrane lipid therapy
  • membrane replacement therapy
  • lipid drug discovery
  • protein-lipid interactions
  • membrane microdomains
  • lipid nanoparticles
  • membrane lipid metabolism

Published Papers (6 papers)

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Research

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16 pages, 2864 KiB  
Article
Anionic Phospholipids Shift the Conformational Equilibrium of the Selectivity Filter in the KcsA Channel to the Conductive Conformation: Predicted Consequences on Inactivation
by María Lourdes Renart, Ana Marcela Giudici, Carlos Coll-Díez, José M. González-Ros and José A. Poveda
Biomedicines 2023, 11(5), 1376; https://doi.org/10.3390/biomedicines11051376 - 05 May 2023
Cited by 1 | Viewed by 1214
Abstract
Here, we report an allosteric effect of an anionic phospholipid on a model K+ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner [...] Read more.
Here, we report an allosteric effect of an anionic phospholipid on a model K+ channel, KcsA. The anionic lipid in mixed detergent–lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner gate is in the open state. Such change consists of increasing the affinity of the channel for K+, stabilizing a conductive-like form by maintaining a high ion occupancy in the SF. The process is highly specific in several aspects: First, lipid modifies the binding of K+, but not that of Na+, which remains unperturbed, ruling out a merely electrostatic phenomenon of cation attraction. Second, no lipid effects are observed when a zwitterionic lipid, instead of an anionic one, is present in the micelles. Lastly, the effects of the anionic lipid are only observed at pH 4.0, when the inner gate of KcsA is open. Moreover, the effect of the anionic lipid on K+ binding to the open channel closely emulates the K+ binding behaviour of the non-inactivating E71A and R64A mutant proteins. This suggests that the observed increase in K+ affinity caused by the bound anionic lipid should result in protecting the channel against inactivation. Full article
(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)
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30 pages, 9472 KiB  
Article
Structural Basis of the Interaction of the G Proteins, Gαi1, Gβ1γ2 and Gαi1β1γ2, with Membrane Microdomains and Their Relationship to Cell Localization and Activity
by Rafael Álvarez and Pablo V. Escribá
Biomedicines 2023, 11(2), 557; https://doi.org/10.3390/biomedicines11020557 - 14 Feb 2023
Cited by 1 | Viewed by 1295
Abstract
GPCRs receive signals from diverse messengers and activate G proteins that regulate downstream signaling effectors. Efficient signaling is achieved through the organization of these proteins in membranes. Thus, protein–lipid interactions play a critical role in bringing G proteins together in specific membrane microdomains [...] Read more.
GPCRs receive signals from diverse messengers and activate G proteins that regulate downstream signaling effectors. Efficient signaling is achieved through the organization of these proteins in membranes. Thus, protein–lipid interactions play a critical role in bringing G proteins together in specific membrane microdomains with signaling partners. Significantly, the molecular basis underlying the membrane distribution of each G protein isoform, fundamental to fully understanding subsequent cell signaling, remains largely unclear. We used model membranes with lipid composition resembling different membrane microdomains, and monomeric, dimeric and trimeric Gi proteins with or without single and multiple mutations to investigate the structural bases of G protein–membrane interactions. We demonstrated that cationic amino acids in the N-terminal region of the Gαi1 and C-terminal region of the Gγ2 subunit, as well as their myristoyl, palmitoyl and geranylgeranyl moieties, define the differential G protein form interactions with membranes containing different lipid classes (PC, PS, PE, SM, Cho) and the various microdomains they may form (Lo, Ld, PC bilayer, charged, etc.). These new findings in part explain the molecular basis underlying amphitropic protein translocation to membranes and localization to different membrane microdomains and the role of these interactions in cell signal propagation, pathophysiology and therapies targeted to lipid membranes. Full article
(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)
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24 pages, 3418 KiB  
Article
Distinct Cellular Tools of Mild Hyperthermia-Induced Acquired Stress Tolerance in Chinese Hamster Ovary Cells
by Ádám Tiszlavicz, Imre Gombos, Mária Péter, Zoltán Hegedűs, Ákos Hunya, Barbara Dukic, István Nagy, Begüm Peksel, Gábor Balogh, Ibolya Horváth, László Vígh and Zsolt Török
Biomedicines 2022, 10(5), 1172; https://doi.org/10.3390/biomedicines10051172 - 19 May 2022
Cited by 1 | Viewed by 1915
Abstract
Mild stress could help cells to survive more severe environmental or pathophysiological conditions. In the current study, we investigated the cellular mechanisms which contribute to the development of stress tolerance upon a prolonged (0–12 h) fever-like (40 °C) or a moderate (42.5 °C) [...] Read more.
Mild stress could help cells to survive more severe environmental or pathophysiological conditions. In the current study, we investigated the cellular mechanisms which contribute to the development of stress tolerance upon a prolonged (0–12 h) fever-like (40 °C) or a moderate (42.5 °C) hyperthermia in mammalian Chinese Hamster Ovary (CHO) cells. Our results indicate that mild heat triggers a distinct, dose-dependent remodeling of the cellular lipidome followed by the expression of heat shock proteins only at higher heat dosages. A significant elevation in the relative concentration of saturated membrane lipid species and specific lysophosphatidylinositol and sphingolipid species suggests prompt membrane microdomain reorganization and an overall membrane rigidification in response to the fluidizing heat in a time-dependent manner. RNAseq experiments reveal that mild heat initiates endoplasmic reticulum stress-related signaling cascades resulting in lipid rearrangement and ultimately in an elevated resistance against membrane fluidization by benzyl alcohol. To protect cells against lethal, protein-denaturing high temperatures, the classical heat shock protein response was required. The different layers of stress response elicited by different heat dosages highlight the capability of cells to utilize multiple tools to gain resistance against or to survive lethal stress conditions. Full article
(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)
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Review

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30 pages, 1840 KiB  
Review
Evolving Diagnostic and Treatment Strategies for Pediatric CNS Tumors: The Impact of Lipid Metabolism
by Paula Fernández-García, Gema Malet-Engra, Manuel Torres, Derek Hanson, Catalina A. Rosselló, Ramón Román, Victoria Lladó and Pablo V. Escribá
Biomedicines 2023, 11(5), 1365; https://doi.org/10.3390/biomedicines11051365 - 05 May 2023
Viewed by 2328
Abstract
Pediatric neurological tumors are a heterogeneous group of cancers, many of which carry a poor prognosis and lack a “standard of care” therapy. While they have similar anatomic locations, pediatric neurological tumors harbor specific molecular signatures that distinguish them from adult brain and [...] Read more.
Pediatric neurological tumors are a heterogeneous group of cancers, many of which carry a poor prognosis and lack a “standard of care” therapy. While they have similar anatomic locations, pediatric neurological tumors harbor specific molecular signatures that distinguish them from adult brain and other neurological cancers. Recent advances through the application of genetics and imaging tools have reshaped the molecular classification and treatment of pediatric neurological tumors, specifically considering the molecular alterations involved. A multidisciplinary effort is ongoing to develop new therapeutic strategies for these tumors, employing innovative and established approaches. Strikingly, there is increasing evidence that lipid metabolism is altered during the development of these types of tumors. Thus, in addition to targeted therapies focusing on classical oncogenes, new treatments are being developed based on a broad spectrum of strategies, ranging from vaccines to viral vectors, and melitherapy. This work reviews the current therapeutic landscape for pediatric brain tumors, considering new emerging treatments and ongoing clinical trials. In addition, the role of lipid metabolism in these neoplasms and its relevance for the development of novel therapies are discussed. Full article
(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)
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10 pages, 1031 KiB  
Review
The Myth of The Annular Lipids
by Juan C. Gómez-Fernández and Félix M. Goñi
Biomedicines 2022, 10(11), 2672; https://doi.org/10.3390/biomedicines10112672 - 22 Oct 2022
Cited by 4 | Viewed by 1790
Abstract
In the early 1970s, the existence of a “lipid annulus” stably surrounding the individual intrinsic protein molecules was proposed by several authors. They referred to a number of lipid molecules in slow exchange with the bulk lipid in the bilayer, i.e., more or [...] Read more.
In the early 1970s, the existence of a “lipid annulus” stably surrounding the individual intrinsic protein molecules was proposed by several authors. They referred to a number of lipid molecules in slow exchange with the bulk lipid in the bilayer, i.e., more or less protein-bound, and more ordered than the bulk lipid. The annular lipids would control enzyme activity. This idea was uncritically accepted by most scientists working with intrinsic membrane proteins at the time, so that the idea operated like a myth in the field. However, in the following decade, hard spectroscopic and biochemical evidence showed that the proposed annular lipids were not immobilized for a sufficiently long time to influence enzyme or transporter activity, nor were they ordered by the protein. Surprisingly, forty years later, the myth survives, and the term ‘annular lipid’ is still in use, in a different, but even more illogical sense. Full article
(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)
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25 pages, 2463 KiB  
Review
Fifty Years of the Fluid–Mosaic Model of Biomembrane Structure and Organization and Its Importance in Biomedicine with Particular Emphasis on Membrane Lipid Replacement
by Garth L. Nicolson and Gonzalo Ferreira de Mattos
Biomedicines 2022, 10(7), 1711; https://doi.org/10.3390/biomedicines10071711 - 15 Jul 2022
Cited by 13 | Viewed by 3566
Abstract
The Fluid–Mosaic Model has been the accepted general or basic model for biomembrane structure and organization for the last 50 years. In order to establish a basic model for biomembranes, some general principles had to be established, such as thermodynamic assumptions, various molecular [...] Read more.
The Fluid–Mosaic Model has been the accepted general or basic model for biomembrane structure and organization for the last 50 years. In order to establish a basic model for biomembranes, some general principles had to be established, such as thermodynamic assumptions, various molecular interactions, component dynamics, macromolecular organization and other features. Previous researchers placed most membrane proteins on the exterior and interior surfaces of lipid bilayers to form trimolecular structures or as lipoprotein units arranged as modular sheets. Such membrane models were structurally and thermodynamically unsound and did not allow independent lipid and protein lateral movements. The Fluid–Mosaic Membrane Model was the only model that accounted for these and other characteristics, such as membrane asymmetry, variable lateral movements of membrane components, cis- and transmembrane linkages and dynamic associations of membrane components into multimolecular complexes. The original version of the Fluid–Mosaic Membrane Model was never proposed as the ultimate molecular description of all biomembranes, but it did provide a basic framework for nanometer-scale biomembrane organization and dynamics. Because this model was based on available 1960s-era data, it could not explain all of the properties of various biomembranes discovered in subsequent years. However, the fundamental organizational and dynamic aspects of this model remain relevant to this day. After the first generation of this model was published, additional data on various structures associated with membranes were included, resulting in the addition of membrane-associated cytoskeletal, extracellular matrix and other structures, specialized lipid–lipid and lipid–protein domains, and other configurations that can affect membrane dynamics. The presence of such specialized membrane domains has significantly reduced the extent of the fluid lipid membrane matrix as first proposed, and biomembranes are now considered to be less fluid and more mosaic with some fluid areas, rather than a fluid matrix with predominantly mobile components. However, the fluid–lipid matrix regions remain very important in biomembranes, especially those involved in the binding and release of membrane lipid vesicles and the uptake of various nutrients. Membrane phospholipids can associate spontaneously to form lipid structures and vesicles that can fuse with various cellular membranes to transport lipids and other nutrients into cells and organelles and expel damaged lipids and toxic hydrophobic molecules from cells and tissues. This process and the clinical use of membrane phospholipid supplements has important implications for chronic illnesses and the support of healthy mitochondria, plasma membranes and other cellular membrane structures. Full article
(This article belongs to the Special Issue Fiftieth Anniversary of the Fluid Mosaic Model of Cell Membranes: From Lipid Structure to Biomedicines)
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