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Trends in Cell Biology May 2020The lipid raft hypothesis postulates that lipid-lipid interactions can laterally organize biological membranes into domains of distinct structures, compositions, and... (Review)
Review
The lipid raft hypothesis postulates that lipid-lipid interactions can laterally organize biological membranes into domains of distinct structures, compositions, and functions. This proposal has in equal measure exhilarated and frustrated membrane research for decades. While the physicochemical principles underlying lipid-driven domains has been explored and is well understood, the existence and relevance of such domains in cells remains elusive, despite decades of research. Here, we review the conceptual underpinnings of the raft hypothesis and critically discuss the supporting and contradicting evidence in cells, focusing on why controversies about the composition, properties, and even the very existence of lipid rafts remain unresolved. Finally, we highlight several recent breakthroughs that may resolve existing controversies and suggest general approaches for moving beyond questions of the existence of rafts and towards understanding their physiological significance.
Topics: Animals; Humans; Membrane Lipids; Membrane Microdomains; Models, Biological; Nanoparticles
PubMed: 32302547
DOI: 10.1016/j.tcb.2020.01.009 -
Drug Target Insights 2020Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which... (Review)
Review
INTRODUCTION
Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes.
METHODS
Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance.
RESULTS
The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption.
CONCLUSION
Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.
PubMed: 33510571
DOI: 10.33393/dti.2020.2185 -
Advances in Experimental Medicine and... 2017The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and... (Review)
Review
The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and intracellular tangles plays a key role in driving the course and progression of the disease. However, there are other biochemical and morphological features of AD, including altered calcium, phospholipid, and cholesterol metabolism and altered mitochondrial dynamics and function that often appear early in the course of the disease, prior to plaque and tangle accumulation. Interestingly, these other functions are associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAM). MAM, which is an intracellular lipid raft-like domain, is closely apposed to mitochondria, both physically and biochemically. These MAM-localized functions are, in fact, increased significantly in various cellular and animal models of AD and in cells from AD patients, which could help explain the biochemical and morphological alterations seen in the disease. Based on these and other observations, a strong argument can be made that increased ER-mitochondria connectivity and increased MAM function are fundamental to AD pathogenesis.
Topics: Alzheimer Disease; Animals; Biological Transport; Brain; Endoplasmic Reticulum; Energy Metabolism; Humans; Membrane Microdomains; Membrane Transport Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitochondrial Proteins; Signal Transduction
PubMed: 28815528
DOI: 10.1007/978-981-10-4567-7_11 -
Biochemistry Dec 2020The time-averaged lateral organization of the lipids and proteins that make up mammalian cell membranes continues to be the subject of intense interest and debate. Since... (Review)
Review
The time-averaged lateral organization of the lipids and proteins that make up mammalian cell membranes continues to be the subject of intense interest and debate. Since the introduction of the fluid mosaic model almost 50 years ago, the "lipid raft hypothesis" has emerged as a popular concept that has captured the imagination of a large segment of the biomembrane community. In particular, the notion that lipid rafts play a pivotal role in cellular processes such as signal transduction and membrane protein trafficking is now favored by many investigators. Despite the attractiveness of lipid rafts, their composition, size, lifetime, biological function, and even the very existence remain controversial. The central tenet that underlies this hypothesis is that cholesterol and high-melting lipids have favorable interactions (i.e., they pull together), which lead to transient domains. Recent nearest-neighbor recognition (NNR) studies have expanded the lipid raft hypothesis to include the influence that low-melting lipids have on the organization of lipid membranes. Specifically, it has been found that mimics of cholesterol and high-melting lipids are repelled (i.e., pushed away) by low-melting lipids in fluid bilayers. The picture that has emerged from our NNR studies is that lipid mixing is governed by a balance of these "push and pull" forces, which maximizes the number of hydrocarbon contacts and attractive van der Waals interactions within the membrane. The power of the NNR methodology is that it allows one to probe these push/pull interaction energies that are measured in tens of calories per mole.
Topics: Animals; Cholesterol; Computer Simulation; Humans; Lipid Bilayers; Membrane Lipids; Membrane Microdomains; Models, Biological; Models, Molecular; Molecular Mimicry; Monte Carlo Method; Phase Transition; Thermodynamics
PubMed: 33226208
DOI: 10.1021/acs.biochem.0c00851 -
Chemical Reviews May 2019To execute their many vital functions, cell membranes are highly organized. Here, we review how membrane structure shapes signal transduction across membranes. Recent... (Review)
Review
To execute their many vital functions, cell membranes are highly organized. Here, we review how membrane structure shapes signal transduction across membranes. Recent experimental and computational advances have shed significant light on mechanisms linking the function of membrane signaling proteins to the composition and physical properties of the membrane lateral structures in which they are embedded. We provide an overview of the structural characteristics of membranes containing heterogeneous mixtures of lipids and other molecules and summarize work on "raft" domains in model and cell membranes, as determined by microscopy, spectroscopy, neutron scattering, and computer simulations. We discuss the principles of partitioning of proteins into membranes and how the structure, dynamics, and function of membrane-embedded and peripheral proteins can be modulated by specific membrane components and physical properties of membranes and raft domains. Finally, we discuss challenges and future directions toward a molecular-level understanding of how membrane organization gives rise to various context-dependent cellular signaling.
Topics: Cell Communication; Cell Membrane; Humans; Lipid Bilayers; Membrane Lipids; Membrane Proteins; Signal Transduction
PubMed: 30747526
DOI: 10.1021/acs.chemrev.8b00439 -
Journal of Cell Science May 2023The formation of membrane vesicles is a common feature in all eukaryotes. Lipid rafts are the best-studied example of membrane domains for both eukaryotes and... (Review)
Review
The formation of membrane vesicles is a common feature in all eukaryotes. Lipid rafts are the best-studied example of membrane domains for both eukaryotes and prokaryotes, and their existence also is suggested in Archaea membranes. Lipid rafts are involved in the formation of transport vesicles, endocytic vesicles, exocytic vesicles, synaptic vesicles and extracellular vesicles, as well as enveloped viruses. Two mechanisms of how rafts are involved in vesicle formation have been proposed: first, that raft proteins and/or lipids located in lipid rafts associate with coat proteins that form a budding vesicle, and second, vesicle budding is triggered by enzymatic generation of cone-shaped ceramides and inverted cone-shaped lyso-phospholipids. In both cases, induction of curvature is also facilitated by the relaxation of tension in the raft domain. In this Review, we discuss the role of raft-derived vesicles in several intracellular trafficking pathways. We also highlight their role in different pathways of endocytosis, and in the formation of intraluminal vesicles (ILVs) through budding inwards from the multivesicular body (MVB) membrane, because rafts inside MVB membranes are likely to be involved in loading RNA into ILVs. Finally, we discuss the association of glycoproteins with rafts via the glycocalyx.
Topics: Endocytosis; Membrane Microdomains; Cell Division; Ceramides; Eukaryota
PubMed: 37158681
DOI: 10.1242/jcs.260887 -
The Journal of Membrane Biology Oct 2022Biomembrane order, dynamics, and other essential physicochemical parameters are controlled by cholesterol, a major component of mammalian cell membranes. Although... (Review)
Review
Biomembrane order, dynamics, and other essential physicochemical parameters are controlled by cholesterol, a major component of mammalian cell membranes. Although cholesterol is well known to exhibit a condensing effect on fluid lipid membranes, the extent of stiffening that occurs with different degrees of lipid acyl chain unsaturation remains an enigma. In this review, we show that cholesterol locally increases the bending rigidity of both unsaturated and saturated lipid membranes, suggesting there may be a length-scale dependence of the bending modulus. We review our published data that address the origin of the mechanical effects of cholesterol on unsaturated and polyunsaturated lipid membranes and their role in biomembrane functions. Through a combination of solid-state deuterium NMR spectroscopy and neutron spin-echo spectroscopy, we show that changes in molecular packing cause the universal effects of cholesterol on the membrane bending rigidity. Our findings have broad implications for the role of cholesterol in lipid-protein interactions as well as raft-like mixtures, drug delivery applications, and the effects of antimicrobial peptides on lipid membranes.
Topics: Animals; Lipid Bilayers; Deuterium; Cholesterol; Cell Membrane; Magnetic Resonance Spectroscopy; Phosphatidylcholines; Mammals
PubMed: 36219221
DOI: 10.1007/s00232-022-00263-9 -
Annual Review of Biophysics May 2017Membrane lipids and cellular water (soft matter) are becoming increasingly recognized as key determinants of protein structure and function. Their influences can be... (Review)
Review
Membrane lipids and cellular water (soft matter) are becoming increasingly recognized as key determinants of protein structure and function. Their influences can be ascribed to modulation of the bilayer properties or to specific binding and allosteric regulation of protein activity. In this review, we first consider hydrophobic matching of the intramembranous proteolipid boundary to explain the conformational changes and oligomeric states of proteins within the bilayer. Alternatively, membranes can be viewed as complex fluids, whose properties are linked to key biological functions. Critical behavior and nonideal mixing of the lipids have been proposed to explain how raft-like microstructures involving cholesterol affect membrane protein activity. Furthermore, the persistence length for lipid-protein interactions suggests the curvature force field of the membrane comes into play. A flexible surface model describes how curvature and hydrophobic forces lead to the emergence of new protein functional states within the membrane lipid bilayer.
Topics: Animals; Hydrophobic and Hydrophilic Interactions; Intracellular Fluid; Lipid Bilayers; Membrane Lipids; Membrane Proteins; Thermodynamics
PubMed: 28532212
DOI: 10.1146/annurev-biophys-070816-033843 -
Journal of Zhejiang University....The identification and use of molecular biomarkers have greatly improved the diagnosis and treatment of malignant tumors. However, a much deeper understanding of... (Review)
Review
The identification and use of molecular biomarkers have greatly improved the diagnosis and treatment of malignant tumors. However, a much deeper understanding of oncogenic proteins is needed for the benefit to cancer patients. The lipid raft marker proteins, flotillin-1 and flotillin-2, were first found in goldfish retinal ganglion cells during axon regeneration. They have since been found in a variety of cells, mainly on the inner surface of cell membranes, and not only act as a skeleton to provide a platform for protein-protein interactions, but also are involved in signal transduction, nerve regeneration, endocytosis, and lymphocyte activation. Previous studies have shown that flotillins are closely associated with tumor development, invasion, and metastasis. In this article, we review the functions of flotillins in relevant cell processes, their underlying mechanisms of action in a variety of tumors, and their potential applications to tumor molecular diagnosis and targeted therapy.
Topics: Animals; Cell Differentiation; Endocytosis; Humans; Membrane Proteins; Neoplasms; Nerve Regeneration
PubMed: 29504311
DOI: 10.1631/jzus.B1700102 -
Current Topics in Membranes 2015The lipid bilayer of the plasma membrane is thought to be compartmentalized by the presence of lipid-protein microdomains. In eukaryotic cells, microdomains composed of... (Review)
Review
The lipid bilayer of the plasma membrane is thought to be compartmentalized by the presence of lipid-protein microdomains. In eukaryotic cells, microdomains composed of sterols and sphingolipids, commonly known as lipid rafts, are believed to exist, and reports on the presence of sterol- or protein-mediated microdomains in bacterial cell membranes are also appearing. Despite increasing attention, little is known about microdomains in the plasma membrane of pathogenic microorganisms. This review attempts to provide an overview of the current state of knowledge of lipid rafts in pathogenic fungi and bacteria. The current literature on characterization of microdomains in pathogens is reviewed, and their potential role in growth, pathogenesis, and drug resistance is discussed. Better insight into the structure and function of membrane microdomains in pathogenic microorganisms might lead to a better understanding of their pathogenesis and development of raft-mediated approaches for therapy.
Topics: Animals; Bacteria; Bacterial Infections; Cholesterol; Drug Resistance; Fungi; Humans; Lipid Bilayers; Membrane Microdomains; Mycoses
PubMed: 26015285
DOI: 10.1016/bs.ctm.2015.03.005