Styrene-maleic acid (SMA) and similar amphiphilic copolymers are known to cut biological membranes into lipid nanoparticles/nanodiscs containing membrane proteins apparently in their relatively ...native membrane lipid environment. Our previous work demonstrated that membrane raft microdomains resist such disintegration by SMA. The use of SMA in studying membrane proteins is limited by its heterogeneity and the inability to prepare defined derivatives. In the present paper, we demonstrate that some amphiphilic peptides structurally mimicking SMA also similarly disintegrate cell membranes. In contrast to the previously used copolymers, the simple peptides are structurally homogeneous. We found that their membrane-disintegrating activity increases with their length (reaching optimum at 24 amino acids) and requires a basic primary structure, that is, (XXD)n, where X represents a hydrophobic amino acid (optimally phenylalanine), D aspartic acid, and n is the number of repeats of these triplets. These peptides may provide opportunities for various well-defined potentially useful modifications in the study of membrane protein biochemistry. Our present results confirm a specific character of membrane raft microdomains.
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Introduction
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Membrane lipid composition
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Membrane lipid structure
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Membrane lipid organization
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Why so many different lipids?
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Lipid mixing and demixing
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Lateral pressure
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Surface ...electrostatics
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Role of lipids in cell functions
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Lipid influence in transmembrane protein function
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Prokaryotic potassium channel (KcsA)
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Mechanosensitive channels
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Voltage‐gated potassium channel (KvAP)
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Nicotinic acetylcholine receptor (nAcChR)
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G protein‐coupled receptors
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Other examples
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Non‐permanent proteins in membranes
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Proteins that interact reversibly with the bilayers
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Proteins that interact irreversibly with the bilayers
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Proteins that interact weakly with the membrane
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Proteins that interact strongly with the membrane
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G proteins and their interactions with membranes
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Small monomeric G proteins: the Ras and Ras‐like family
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Protein kinase C
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Membrane microdomains and lipid mediators in the control of heat‐shock protein response
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Stress sensing and signalling: the membrane sensor theory
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Hsp signalling in cancer and diabetes
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The role of membrane microdomains
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Lipid mediators of the stress response
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A subpopulation of Hsps can interact with and translocate through membranes
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Hsp90 in eukaryotic membranes
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Hsp70 in cell membranes
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Hsp27‐membrane interactions
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Secreted Hsps
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Representative cases where Hsps interact with membranes or release from the cells
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Concluding remarks
Membranes constitute a meeting point for lipids and proteins. Not only do they define the entity of cells and cytosolic organelles but they also display a wide variety of important functions previously ascribed to the activity of proteins alone. Indeed, lipids have commonly been considered a mere support for the transient or permanent association of membrane proteins, while acting as a selective cell/organelle barrier. However, mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains that serve as spatio‐temporal platforms for interacting signalling proteins. Membrane lipids are crucial in the fission and fusion of lipid bilayers and they also act as sensors to control environmental or physiological conditions. Lipids and lipid structures participate directly as messengers or regulators of signal transduction. Moreover, their alteration has been associated with the development of numerous diseases. Proteins can interact with membranes through lipid co‐/post‐translational modifications, and electrostatic and hydrophobic interactions, van der Waals forces and hydrogen bonding are all involved in the associations among membrane proteins and lipids. The present study reviews these interactions from the molecular and biomedical point of view, and the effects of their modulation on the physiological activity of cells, the aetiology of human diseases and the design of clinical drugs. In fact, the influence of lipids on protein function is reflected in the possibility to use these molecular species as targets for therapies against cancer, obesity, neurodegenerative disorders, cardiovascular pathologies and other diseases, using a new approach called membrane‐lipid therapy.
Recently, a novel cyclo-heptapeptide composed of alternating D,L-amino acids and a unique thiazolidine heterocycle, called lugdunin, was discovered, which is produced by the nasal and skin commensal ...Staphylococcus lugdunensis. Lugdunin displays potent antimicrobial activity against a broad spectrum of Gram-positive bacteria, including challenging-to-treat methicillin-resistant Staphylococcus aureus (MRSA). Lugdunin specifically inhibits target bacteria by dissipating their membrane potential. However, the precise mode of action of this new class of fibupeptides remains largely elusive. Here, we disclose the mechanism by which lugdunin rapidly destabilizes the bacterial membrane potential using an in vitro approach. The peptide strongly partitions into lipid compositions resembling Gram-positive bacterial membranes but less in those harboring the eukaryotic membrane component cholesterol. Upon insertion, lugdunin forms hydrogen-bonded antiparallel β-sheets by the formation of peptide nanotubes, as demonstrated by ATR-FTIR spectroscopy and molecular dynamics simulations. These hydrophilic nanotubes filled with a water wire facilitate not only the translocation of protons but also of monovalent cations as demonstrated by voltage-clamp experiments on black lipid membranes. Collectively, our results provide evidence that the natural fibupeptide lugdunin acts as a peptidic channel that is spontaneously formed by an intricate stacking mechanism, leading to the dissipation of a bacterial cell's membrane potential.
The process of protein transport across membranes involves a variety of factors and has been extensively investigated. Traditionally, proteinaceous translocons and chaperones have been recognized as ...crucial factors in this process. However, recent studies have highlighted the significant roles played by lipids and a glycolipid present in biological membranes in membrane protein transport. Membrane lipids can influence transport efficiency by altering the physicochemical properties of membranes. Notably, our studies have revealed that diacylglycerol (DAG) attenuates mobility in the membrane core region, leading to a dramatic suppression of membrane protein integration. Conversely, a glycolipid in Escherichia coli inner membranes, named membrane protein integrase (MPIase), enhances integration not only through the alteration of membrane properties but also via direct interactions with membrane proteins. This review explores the mechanisms of membrane protein integration mediated by membrane lipids, specifically DAG, and MPIase. Our results, along with the employed physicochemical analysis methods such as fluorescence measurements, nuclear magnetic resonance, surface plasmon resonance, and docking simulation, are presented to elucidate these mechanisms.
In Escherichia coli inner membranes, diacylglycerol (DAG) and a glycolipid, named membrane protein integrase (MPIase), particularly influence membrane protein transport. This review explores the mechanisms of membrane protein integration mediated by these factors, and the methods and results of physicochemical analysis are presented.
Research investigating lipid membrane curvature generation and sensing is a rapidly developing frontier in membrane physical chemistry and biophysics. The fast recent progress is based on the ...discovery of a plethora of proteins involved in coupling membrane shape to cellular membrane function, the design of new quantitative experimental techniques to study aspects of membrane curvature, and the development of analytical theories and simulation techniques that allow a mechanistic interpretation of quantitative measurements. The present review first provides an overview of important classes of membrane proteins for which function is coupled to membrane curvature. We then survey several mechanisms that are assumed to underlie membrane curvature sensing and generation. Finally, we discuss relatively simple thermodynamic/mechanical models that allow quantitative interpretation of experimental observations.
The unfolded protein response (UPR) is a conserved homeostatic program that is activated by misfolded proteins in the lumen of the endoplasmic reticulum (ER). Recently, it became evident that ...aberrant lipid compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent in activating the UPR. The underlying molecular mechanism, however, remained unclear. We show that the most conserved transducer of ER stress, Ire1, uses an amphipathic helix (AH) to sense membrane aberrancies and control UPR activity. In vivo and in vitro experiments, together with molecular dynamics (MD) simulations, identify the physicochemical properties of the membrane environment that control Ire1 oligomerization. This work establishes the molecular mechanism of UPR activation by lipid bilayer stress.
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•Aberrant lipid compositions of the ER activate the unfolded protein response•Ire1 integrates two forms of ER stress: unfolded proteins and lipid bilayer stress•Ire1 uses an amphipathic helix to sense aberrant physical membrane properties•Local bilayer compression by Ire1 controls its membrane-sensitive activation
The unfolded protein response (UPR) controls the secretory capacity of a cell and is activated by accumulating unfolded proteins in the lumen of the ER. More recently, it became obvious that aberrant membrane lipid compositions of the ER are equally potent in activating the UPR. Halbleib et al. identify a membrane-based mechanism of UPR activation and establish that Ire1, the most conserved transducer of ER stress, uses an amphipathic helix to sense and respond to aberrant physical properties of the ER membrane.
Biomimetic nanotechnology through camouflaging synthetic nanoparticles (NPs) with natural cell membranes, which bestows with immune evasion and superior targeting capacity, has been extensively used ...in drug delivery systems (DDS) over the last decades. These biomimetic NPs not only retain the physicochemical features of the synthetic vehicles but also inherit the cell membranes' intrinsic functionalities. Combined with these benefits, optimized nano-biomimetic DDS allow maximum delivery efficacy. Compared to erythrocyte/cancer single cell membrane, the hybrid cell membrane expressing CD47 membrane protein and self-recognition molecules, from erythrocytes and cancer cells, provides remarkable features to the synthetic vehicles, such as immune evasion, long-term circulation, and homotypic targeting. In this review, we describe the preparation strategies, the camouflaging mechanism, and the antitumor applications of hybrid cell membrane-camouflaged NPs. Moreover, we discuss further modification of the hybrid cell membrane and the surface properties of fusion cellular membranes. Finally, we summarize the primary challenges and opportunities associated with these NPs. STATEMENT OF SIGNIFICANCE: Camouflaging synthetic nanoparticles with hybrid cell membrane has been extensively highlighted in recent years. The resultant biomimetic nanoparticles not only reserve the physicochemical properties of the synthetic nanoparticles but also inherit the biological functions of source cells. Compared with single cell membrane, hybrid cell membrane can endow synthetic nanoparticles with multiple biofunctions derived from the original source cells. To provide a timely review of this rapidly developing subject of research, this paper summarized recent progress on the hybrid cell membrane-camouflaged nanoparticles as drug delivery systems for cancer diagnosis and treatment. In this review, we focused primarily on five different types of hybrid cell membrane-camouflaged nanoparticles with the preparation strategies, the camouflaging mechanism, and the antitumor applications. Moreover, further modification of the hybrid cell membrane was also discussed for isolating effectively circulating tumor cells.
Early studies have revealed that some mammalian plasma membrane proteins exist in small nanoclusters. The advent of super-resolution microscopy has corroborated and extended this picture, and led to ...the suggestion that many, if not most, membrane proteins are clustered at the plasma membrane at nanoscale lengths. In this Commentary, we present selected examples of glycosylphosphatidyl-anchored proteins, Ras family members and several immune receptors that provide evidence for nanoclustering. We advocate the view that nanoclustering is an important part of the hierarchical organization of proteins in the plasma membrane. According to this emerging picture, nanoclusters can be organized on the mesoscale to form microdomains that are capable of supporting cell adhesion, pathogen binding and immune cell-cell recognition amongst other functions. Yet, a number of outstanding issues concerning nanoclusters remain open, including the details of their molecular composition, biogenesis, size, stability, function and regulation. Notions about these details are put forth and suggestions are made about nanocluster function and why this general feature of protein nanoclustering appears to be so prevalent.
HIV-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the ...intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor.
We present a molecular modeling and simulation study of the E. coli cell envelope, with a particular focus on the role of TolR, a native protein of the E. coli inner membrane, in interactions with ...the cell wall. TolR has been proposed to bind to peptidoglycan, but the only structure of this protein thus far is in a conformation in which the putative peptidoglycan binding domain is not accessible. We show that a model of the extended conformation of the protein in which this domain is exposed binds peptidoglycan largely through electrostatic interactions. Non-covalent interactions of TolR and OmpA with the cell wall, from the inner membrane and outer membrane sides, respectively, maintain the position of the cell wall even in the absence of Braun's lipoprotein. The charged residues that mediate the cell-wall interactions of TolR in our simulations are conserved across a number of species of gram-negative bacteria.
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•TolR binds peptidoglycan cell wall via electrostatic interactions•Binding of TolR and OmpA keeps the cell wall flat•Closed-state TolR does not interact with the cell wall•Cell-wall-binding residues of TolR conserved across species
By performing atomistic simulations of a gram-negative bacterial cell envelope, Boags et al. reveal the importance of protein binding from both the inner and the outer membrane sides in preserving the structural integrity of the peptidoglycan cell wall.
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