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Handbook of Experimental Pharmacology 2024The transmembrane protein 16 (TMEM16) family consists of Ca-activated chloride channels and phospholipid scramblases. Ten mammalian TMEM16 proteins, TMEM16A-K (with no... (Review)
Review
The transmembrane protein 16 (TMEM16) family consists of Ca-activated chloride channels and phospholipid scramblases. Ten mammalian TMEM16 proteins, TMEM16A-K (with no TMEM16I), and several non-mammalian TMEM16 proteins, such as afTMEM16 and nhTMEM16, have been discovered. All known TMEM16 proteins are homodimeric proteins containing two subunits. Each subunit consists of ten transmembrane helices with Ca-binding sites and a single ion-permeation/phospholipid transport pathway. The ion-permeation pathway and the phospholipid transport pathway of TMEM16 proteins have a wide intracellular vestibule, a narrow neck, and a smaller extracellular vestibule. Interestingly, the lining wall of the ion-permeation/phospholipid transport pathway may be formed, at least partially, by membrane phospholipids, though the degree of pore-wall forming by phospholipids likely varies among TMEM16 proteins. Thus, the biophysical properties and activation mechanisms of TMEM16 proteins could differ from each other accordingly. Here we review the current understanding of the structure and function of TMEM16 molecules.
Topics: Humans; Animals; Chloride Channels; Phospholipid Transfer Proteins; Anoctamins; Ion Transport; Phospholipids; Calcium; Mammals
PubMed: 35792944
DOI: 10.1007/164_2022_595 -
Nature Structural & Molecular Biology Apr 2024Class C G-protein-coupled receptors (GPCRs) are activated through binding of agonists to the large extracellular domain (ECD) followed by rearrangement of the...
Class C G-protein-coupled receptors (GPCRs) are activated through binding of agonists to the large extracellular domain (ECD) followed by rearrangement of the transmembrane domains (TMDs). GPR156, a class C orphan GPCR, is unique because it lacks an ECD and exhibits constitutive activity. Impaired GPR156-G signaling contributes to loss of hearing. Here we present the cryo-electron microscopy structures of human GPR156 in the G-free and G-coupled states. We found that an endogenous phospholipid molecule is located within each TMD of the GPR156 dimer. Asymmetric binding of Gα to the phospholipid-bound GPR156 dimer restructures the first and second intracellular loops and the carboxy-terminal part of the elongated transmembrane 7 (TM7) without altering dimer conformation. Our findings reveal that GPR156 is a transducer for phospholipid signaling. Constant binding of abundant phospholipid molecules and the G-protein-induced reshaping of the cytoplasmic face provide a basis for the constitutive activation of GPR156.
Topics: Humans; Cryoelectron Microscopy; Receptors, G-Protein-Coupled; Signal Transduction; GTP-Binding Proteins; Phospholipids
PubMed: 38332368
DOI: 10.1038/s41594-024-01224-7 -
Accounts of Chemical Research Nov 2023The abrupt aggregation of misfolded proteins is linked to the onset and spread of amyloidogenic diseases, including diabetes type 2, systemic amyloidosis, and...
The abrupt aggregation of misfolded proteins is linked to the onset and spread of amyloidogenic diseases, including diabetes type 2, systemic amyloidosis, and Alzheimer's (AD) and Parkinson's diseases (PD). Although the exact cause of these pathological processes is unknown, a growing body of evidence suggests that amyloid diseases are triggered by misfolded or unfolded proteins, forming highly toxic oligomers. These transient species exhibit high structural and morphological heterogeneity. Protein oligomers can also propagate into β-sheet-rich filaments that braid and coil with other filaments to form amyloid fibrils and supramolecular structures with both flat and twisted morphologies. Microscopic examination of protein deposits formed in the brains of both AD and PD patients revealed the presence of fragments of lipid membranes. Furthermore, nanoscale infrared analysis of extracted fibrils revealed the presence of lipids in their structure (Zhaliazka, K.; Kurouski, D. , , e4598). These findings demonstrated that lipid bilayers could play an important role in the aggregation of misfolded proteins.Experimental findings summarized in this Account show that (i) lipids uniquely change the aggregation rate of amyloidogenic proteins. In this case, the observed changes in the rates directly depend on the net charge of the lipid and the length and saturation of lipid fatty acids (FAs). For instance, zwitterionic phosphatidylcholine (PC) with 14:0 FAs inhibited the aggregation of insulin, lysozyme, and α-synuclein (α-Syn), whereas anionic phosphatidylserine with the same FAs dramatically accelerated the aggregation rate of these proteins (Dou, T., et al. , , 4407. Matveyenka, M., et al. , , e22543. Rizevsky, S., et al. , , 2467). Furthermore, (ii) lipids uniquely alter the secondary structure and morphology of protein oligomers and fibrils formed in their presence. Utilization of nano-infrared spectroscopy revealed that such aggregates, as well as extracted fibrils, possessed lipids in their structure. These findings are significant because (iii) lipids uniquely alter the toxicity of amyloid oligomers and fibrils formed in their presence. Specifically, PC lowered the toxicity of insulin and lysozyme oligomers, whereas α-Syn oligomers formed in the presence of this phospholipid were found to be significantly more toxic to rat dopaminergic cells compared to α-Syn oligomers grown in the lipid-free environment. Thus, the toxicity of protein oligomers and fibrils is directly determined by the chemical structure of the lipid and the secondary structure of amyloidogenic proteins (Dou, T., et al. , , 4407. Matveyenka, M., et al. , , e22543. Rizevsky, S., et al. , , 2467). Experimental results discussed in this Account also suggest that amyloidogenic diseases could be caused by pathological changes in the lipid composition of both plasma and organelle membranes, which, in turn, may trigger protein aggregation that results in the formation of highly toxic oligomers and fibrils. Finally, the Account discusses the effects of polyunsaturated FAs on the aggregation properties of amyloidogenic proteins. Experimental findings reported by the author's laboratory revealed that polyunsaturated FAs drastically accelerated the aggregation rate of both insulin and α-Syn as well as strongly changed the secondary structure of amyloid fibrils formed in their presence.
Topics: Humans; Animals; Rats; Amyloidogenic Proteins; Muramidase; Parkinson Disease; Amyloid; Phospholipids; Insulins
PubMed: 37824095
DOI: 10.1021/acs.accounts.3c00386 -
Biochemical Pharmacology Jul 2023Mammalian cells contain more than a thousand different glycerophospholipid species that are essential membrane components and signalling molecules, with... (Review)
Review
Mammalian cells contain more than a thousand different glycerophospholipid species that are essential membrane components and signalling molecules, with phosphatidylserine (PS) giving membranes their negative surface charge. Depending on the tissue, PS is important in apoptosis, blood clotting, cancer pathogenesis, as well as muscle and brain function, processes that are dependent on the asymmetrical distribution of PS on the plasma membrane and/or the capacity of PS to act as anchorage for various signalling proteins. Recent studies have implicated hepatic PS in the progression of non-alcoholic fatty liver disease (NAFLD), either as beneficial in the context of suppressing hepatic steatosis and fibrosis, or on the other hand as a potential contributor to the progression of liver cancer. This review provides an extensive overview of hepatic phospholipid metabolism, including its biosynthetic pathways, intracellular trafficking and roles in health and disease, further taking a deeper dive into PS metabolism, including associate and causative evidence of the role of PS in advanced liver disease.
Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Phosphatidylserines; Liver; Liver Neoplasms; Phospholipids; Lipid Metabolism; Mammals
PubMed: 37217141
DOI: 10.1016/j.bcp.2023.115621 -
Advanced Drug Delivery Reviews Aug 2023Long-acting injectable (LAIs) delivery systems sustain the drug therapeutic action in the body, resulting in reduced dosage regimen, toxicity, and improved patient... (Review)
Review
Long-acting injectable (LAIs) delivery systems sustain the drug therapeutic action in the body, resulting in reduced dosage regimen, toxicity, and improved patient compliance. Lipid-based depots are biocompatible, provide extended drug release, and improve drug stability, making them suitable for systemic and localized treatment of various chronic ailments, including psychosis, diabetes, hormonal disorders, arthritis, ocular diseases, and cancer. These depots include oil solutions, suspensions, oleogels, liquid crystalline systems, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, phospholipid phase separation gel, vesicular phospholipid gel etc. This review summarizes recent advancements in lipid-based LAIs for delivering small and macromolecules, and their potential in managing chronic diseases. It also provides an overview of the lipid depots available in market or clinical phase, as well as patents for lipid-based LAIs. Furthermore, this review critically discusses the current scenario of using in vitro release methods to establish IVIVC and highlights the challenges involved in developing lipid-based LAIs.
Topics: Humans; Phospholipids; Nanostructures; Delayed-Action Preparations
PubMed: 37257756
DOI: 10.1016/j.addr.2023.114901 -
International Journal of Molecular... Nov 2023The overuse and misuse of antibiotics have led to the emergence and spread of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR)... (Review)
Review
The overuse and misuse of antibiotics have led to the emergence and spread of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) bacteria strains, usually associated with poorer patient outcomes and higher costs. In order to preserve the usefulness of these life-saving drugs, it is crucial to use them appropriately, as also recommended by the WHO. Moreover, innovative, safe, and more effective approaches are being investigated, aiming to revise drug treatments to improve their pharmacokinetics and distribution and to reduce the onset of drug resistance. Globally, to reduce the burden of antimicrobial resistance (AMR), guidelines and indications have been developed over time, aimed at narrowing the use and diminishing the environmental spread of these life-saving molecules by optimizing prescriptions, dosage, and times of use, as well as investing resources into obtaining innovative formulations with better pharmacokinetics, pharmacodynamics, and therapeutic results. This has led to the development of new nano-formulations as drug delivery vehicles, characterized by unique structural properties, biocompatible natures, and targeted activities such as state-of-the-art phospholipid particles generally grouped as liposomes, virosomes, and functionalized exosomes, which represent an attractive and innovative delivery approach. Liposomes and virosomes are chemically synthesized carriers that utilize phospholipids whose nature is predetermined based on their use, with a long track record as drug delivery systems. Exosomes are vesicles naturally released by cells, which utilize the lipids present in their cellular membranes only, and therefore, are highly biocompatible, with investigations as a delivery system having a more recent origin. This review will summarize the state of the art on microvesicle research, liposomes, virosomes, and exosomes, as useful and effective tools to tackle the threat of antibiotic resistance.
Topics: Humans; Anti-Bacterial Agents; Liposomes; Phospholipids; Virosomes; Drug Resistance, Bacterial; Bacteria
PubMed: 37958915
DOI: 10.3390/ijms242115934 -
Chemical Communications (Cambridge,... Aug 2023This Feature Article focuses on recent studies on the development of self-assembling materials that mimic and control dynamic bio-interfaces. Extracellular matrix (ECM)... (Review)
Review
This Feature Article focuses on recent studies on the development of self-assembling materials that mimic and control dynamic bio-interfaces. Extracellular matrix (ECM) is a fundamental tissue at the cellular interface constructed by networks of fibrous proteins, which regulates a variety of cellular activities. Reconstruction of ECM has been demonstrated by self-assembling peptides. By combining the dynamic properties of the self-assembling peptides conjugated with full-length proteins, peptide-based supramolecular materials enable neuronal migration and regeneration of injured neural tissue. The phospholipid bilayer is the main component of the cell membrane. The morphology and deformation of the phospholipid bilayer relate directly to dynamic interfacial functions. Stabilization of the phospholipid nanosheet structure has been demonstrated by self-assembling peptides, and the stabilized bicelle is functional for extended blood circulation. By using a photo-responsive synthetic surfactant showing a mechanical opening/closing motion, endocytosis-like outside-in membrane deformation is triggered. The outside-in deformation allows for efficient encapsulation of micrometer-size substances such as phage viruses into the liposomes, and the encapsulated viruses can be delivered to multiple organs in a living body blood administration. These supramolecular approaches to mimicking and controlling bio-interfaces present powerful ways to develop unprecedented regenerative medicines and drug delivery systems.
Topics: Phospholipids; Peptides; Extracellular Matrix; Cell Membrane; Biocompatible Materials
PubMed: 37440181
DOI: 10.1039/d3cc01875j -
Proceedings of the National Academy of... Feb 2024Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification...
Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.
Topics: Humans; Phospholipids; Histones; Cell Differentiation; T-Lymphocytes; Autoimmune Diseases
PubMed: 38359295
DOI: 10.1073/pnas.2314561121 -
Chemistry and Physics of Lipids Sep 2023Drug delivery through the skin improves solubility, bioavailability, and unwanted systemic side effects of the drug. The selection of a suitable carrier is a challenging... (Review)
Review
Drug delivery through the skin improves solubility, bioavailability, and unwanted systemic side effects of the drug. The selection of a suitable carrier is a challenging process. The conventional lipid vesicles have some limitations. They deliver the drug in the stratum corneum and have poor colloidal stability. Here comes the need for ultra-deformable lipid vesicles to provide the drug beyond the stratum corneum. Transethosomes are novel ultra-deformable vesicles that can deliver drugs into deeper tissues. The composition of transethosomes includes phospholipid, ethanol and surfactants. Each ingredient has a pivotal role in the properties of the carrier. This review covers the design, preparation method, characterisation, and characteristics of the novel vesicle. Also, we cover the impact of surfactants on vesicular properties and the skin permeation behaviour of novel vesicles.
Topics: Skin Absorption; Administration, Cutaneous; Skin; Drug Delivery Systems; Phospholipids; Ethanol; Surface-Active Agents; Drug Carriers; Liposomes
PubMed: 37356610
DOI: 10.1016/j.chemphyslip.2023.105315 -
Nature Chemistry Jul 2023Cellular membranes contain numerous lipid species, and efforts to understand the biological functions of individual lipids have been stymied by a lack of approaches for...
Cellular membranes contain numerous lipid species, and efforts to understand the biological functions of individual lipids have been stymied by a lack of approaches for controlled modulation of membrane composition in situ. Here we present a strategy for editing phospholipids, the most abundant lipids in biological membranes. Our membrane editor is based on a bacterial phospholipase D (PLD), which exchanges phospholipid head groups through hydrolysis or transphosphatidylation of phosphatidylcholine with water or exogenous alcohols. Exploiting activity-dependent directed enzyme evolution in mammalian cells, we have developed and structurally characterized a family of 'superPLDs' with up to a 100-fold enhancement in intracellular activity. We demonstrate the utility of superPLDs for both optogenetics-enabled editing of phospholipids within specific organelle membranes in live cells and biocatalytic synthesis of natural and unnatural designer phospholipids in vitro. Beyond the superPLDs, activity-based directed enzyme evolution in mammalian cells is a generalizable approach to engineer additional chemoenzymatic biomolecule editors.
Topics: Animals; Phospholipids; Phosphatidylcholines; Cell Membrane; Phospholipase D; Hydrolysis; Mammals
PubMed: 37217787
DOI: 10.1038/s41557-023-01214-0