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Journal of Lipid Research May 2005Lipids are produced, transported, and recognized by the concerted actions of numerous enzymes, binding proteins, and receptors. A comprehensive analysis of lipid... (Review)
Review
Lipids are produced, transported, and recognized by the concerted actions of numerous enzymes, binding proteins, and receptors. A comprehensive analysis of lipid molecules, "lipidomics," in the context of genomics and proteomics is crucial to understanding cellular physiology and pathology; consequently, lipid biology has become a major research target of the postgenomic revolution and systems biology. To facilitate international communication about lipids, a comprehensive classification of lipids with a common platform that is compatible with informatics requirements has been developed to deal with the massive amounts of data that will be generated by our lipid community. As an initial step in this development, we divide lipids into eight categories (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides) containing distinct classes and subclasses of molecules, devise a common manner of representing the chemical structures of individual lipids and their derivatives, and provide a 12 digit identifier for each unique lipid molecule. The lipid classification scheme is chemically based and driven by the distinct hydrophobic and hydrophilic elements that compose the lipid. This structured vocabulary will facilitate the systematization of lipid biology and enable the cataloging of lipids and their properties in a way that is compatible with other macromolecular databases.
Topics: Database Management Systems; Lipids; Molecular Structure; Terminology as Topic
PubMed: 15722563
DOI: 10.1194/jlr.E400004-JLR200 -
Cell Structure and Function May 2023Protein-lipid conjugation is a widespread modification involved in many biological processes. Various lipids, including fatty acids, isoprenoids, sterols,... (Review)
Review
Protein-lipid conjugation is a widespread modification involved in many biological processes. Various lipids, including fatty acids, isoprenoids, sterols, glycosylphosphatidylinositol, sphingolipids, and phospholipids, are covalently linked with proteins. These modifications direct proteins to intracellular membranes through the hydrophobic nature of lipids. Some of these membrane-binding processes are reversible through delipidation or by reducing the affinity to membranes. Many signaling molecules undergo lipid modification, and their membrane binding is important for proper signal transduction. The conjugation of proteins to lipids also influences the dynamics and function of organellar membranes. Dysregulation of lipidation has been associated with diseases such as neurodegenerative diseases. In this review, we first provide an overview of diverse forms of protein-lipid conjugation and then summarize the catalytic mechanisms, regulation, and roles of these modifications.Key words: lipid, lipidation, membrane, organelle, protein modification.
Topics: Proteins; Fatty Acids; Phospholipids; Lipid Metabolism; Sterols; Cell Membrane
PubMed: 37019684
DOI: 10.1247/csf.23016 -
Progress in Lipid Research Jan 2022This review examines lipids and lipid-binding sites on proteins in relation to cardiovascular disease. Lipid nutrition involves food energy from ingested fatty acids... (Review)
Review
This review examines lipids and lipid-binding sites on proteins in relation to cardiovascular disease. Lipid nutrition involves food energy from ingested fatty acids plus fatty acids formed from excess ingested carbohydrate and protein. Non-esterified fatty acids (NEFA) and lipoproteins have many detailed attributes not evident in their names. Recognizing attributes of lipid-protein interactions decreases unexpected outcomes. Details of double bond position and configuration interacting with protein binding sites have unexpected consequences in acyltransferase and cell replication events. Highly unsaturated fatty acids (HUFA) have n-3 and n-6 motifs with documented differences in intensity of destabilizing positive feedback loops amplifying pathophysiology. However, actions of NEFA have been neglected relative to cholesterol, which is co-produced from excess food. Native low-density lipoproteins (LDL) bind to a high-affinity cell surface receptor which poorly recognizes biologically modified LDLs. NEFA increase negative charge of LDL and decrease its processing by "normal" receptors while increasing processing by "scavenger" receptors. A positive feedback loop in the recruitment of monocytes and macrophages amplifies chronic inflammatory pathophysiology. Computer tools combine multiple components in lipid nutrition and predict balance of energy and n-3:n-6 HUFA. The tools help design and execute precise clinical nutrition monitoring that either supports or disproves expectations.
Topics: Fatty Acids; Fatty Acids, Nonesterified; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Lipoproteins, LDL
PubMed: 34818526
DOI: 10.1016/j.plipres.2021.101142 -
Journal of the American Chemical Society Sep 2021Interest in lipid interactions with proteins and other biomolecules is emerging not only in fundamental biochemistry but also in the field of nanobiotechnology where...
Interest in lipid interactions with proteins and other biomolecules is emerging not only in fundamental biochemistry but also in the field of nanobiotechnology where lipids are commonly used, for example, in carriers of mRNA vaccines. The outward-facing components of cellular membranes and lipid nanoparticles, the lipid headgroups, regulate membrane interactions with approaching substances, such as proteins, drugs, RNA, or viruses. Because lipid headgroup conformational ensembles have not been experimentally determined in physiologically relevant conditions, an essential question about their interactions with other biomolecules remains unanswered: Do headgroups exchange between a few rigid structures, or fluctuate freely across a practically continuous spectrum of conformations? Here, we combine solid-state NMR experiments and molecular dynamics simulations from the NMRlipids Project to resolve the conformational ensembles of headgroups of four key lipid types in various biologically relevant conditions. We find that lipid headgroups sample a wide range of overlapping conformations in both neutral and charged cellular membranes, and that differences in the headgroup chemistry manifest only in probability distributions of conformations. Furthermore, the analysis of 894 protein-bound lipid structures from the Protein Data Bank suggests that lipids can bind to proteins in a wide range of conformations, which are not limited by the headgroup chemistry. We propose that lipids can select a suitable headgroup conformation from the wide range available to them to fit the various binding sites in proteins. The proposed will extend also to lipid binding to targets other than proteins, such as drugs, RNA, and viruses.
Topics: Lipids; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Phosphatidylcholines; Phosphatidylglycerols; Protein Binding; Proteins
PubMed: 34465095
DOI: 10.1021/jacs.1c05549 -
PLoS Neglected Tropical Diseases Mar 2015The hydatid disease parasite Echinococcus granulosus has a restricted lipid metabolism, and needs to harvest essential lipids from the host. Antigen B (EgAgB), an...
BACKGROUND
The hydatid disease parasite Echinococcus granulosus has a restricted lipid metabolism, and needs to harvest essential lipids from the host. Antigen B (EgAgB), an abundant lipoprotein of the larval stage (hydatid cyst), is thought to be important in lipid storage and transport. It contains a wide variety of lipid classes, from highly hydrophobic compounds to phospholipids. Its protein component belongs to the cestode-specific Hydrophobic Ligand Binding Protein family, which includes five 8-kDa isoforms encoded by a multigene family (EgAgB1-EgAgB5). How lipid and protein components are assembled into EgAgB particles remains unknown. EgAgB apolipoproteins self-associate into large oligomers, but the functional contribution of lipids to oligomerization is uncertain. Furthermore, binding of fatty acids to some EgAgB subunits has been reported, but their ability to bind other lipids and transfer them to acceptor membranes has not been studied.
METHODOLOGY/PRINCIPAL FINDINGS
Lipid-free EgAgB subunits obtained by reverse-phase HPLC were used to analyse their oligomerization, ligand binding and membrane interaction properties. Size exclusion chromatography and cross-linking experiments showed that EgAgB8/2 and EgAgB8/3 can self-associate, suggesting that lipids are not required for oligomerization. Furthermore, using fluorescent probes, both subunits were found to bind fatty acids, but not cholesterol analogues. Analysis of fatty acid transfer to phospholipid vesicles demonstrated that EgAgB8/2 and EgAgB8/3 are potentially capable of transferring fatty acids to membranes, and that the efficiency of transfer is dependent on the surface charge of the vesicles.
CONCLUSIONS/SIGNIFICANCE
We show that EgAgB apolipoproteins can oligomerize in the absence of lipids, and can bind and transfer fatty acids to phospholipid membranes. Since imported fatty acids are essential for Echinococcus granulosus, these findings provide a mechanism whereby EgAgB could engage in lipid acquisition and/or transport between parasite tissues. These results may therefore indicate vulnerabilities open to targeting by new types of drugs for hydatidosis therapy.
Topics: Amino Acid Sequence; Animals; Echinococcosis; Fatty Acids; Humans; Lipids; Lipoproteins; Membranes; Molecular Sequence Data; Phospholipids; Polymerization; Protein Subunits
PubMed: 25768648
DOI: 10.1371/journal.pntd.0003552 -
Protein Science : a Publication of the... Jun 2020Our understanding of the plasma membrane structure has undergone a major change since the proposal of the fluid mosaic model of Singer and Nicholson in the 1970s. In... (Review)
Review
Our understanding of the plasma membrane structure has undergone a major change since the proposal of the fluid mosaic model of Singer and Nicholson in the 1970s. In this model, the membrane, composed of over thousand lipid and protein species, is organized as a well-equilibrated two-dimensional fluid. Here, the distribution of lipids is largely expected to reflect a multicomponent system, and proteins are expected to be surrounded by an annulus of specialized lipid species. With the recognition that a multicomponent lipid membrane is capable of phase segregation, the membrane is expected to appear as patchwork quilt pattern of membrane domains. However, the constituents of a living membrane are far from being well equilibrated. The living cell membrane actively maintains a trans-bilayer asymmetry of composition, and its constituents are subject to a number of dynamic processes due to synthesis, lipid transfer as well as membrane traffic and turnover. Moreover, membrane constituents engage with the dynamic cytoskeleton of a living cell, and are both passively as well as actively manipulated by this engagement. The extracellular matrix and associated elements also interact with membrane proteins contributing to another layer of interaction. At the nano- and mesoscale, the organization of lipids and proteins emerge from these encounters, as well as from protein-protein, protein-lipid, and lipid-lipid interactions in the membrane. New methods to study the organization of membrane components at these scales have also been developed, and provide an opportunity to synthesize a new picture of the living cell surface as an active membrane composite.
Topics: Animals; Cell Membrane; Humans; Lipids; Membrane Lipids
PubMed: 32297381
DOI: 10.1002/pro.3874 -
Cold Spring Harbor Perspectives in... Jan 2020Phosphatase and tensin homolog deleted on chromosome 10 () encodes a 403-amino acid protein with an amino-terminal domain that shares sequence homology with the... (Review)
Review
Phosphatase and tensin homolog deleted on chromosome 10 () encodes a 403-amino acid protein with an amino-terminal domain that shares sequence homology with the actin-binding protein tensin and the putative tyrosine-protein phosphatase auxilin. Crystal structure analysis of PTEN has revealed a C2 domain that binds to phospholipids in membranes and a phosphatase domain that displays dual-specific activity toward both tyrosine (Y), serine (S)/threonine (T), as well as lipid substrates in vitro. Characterized primarily as a lipid phosphatase, PTEN plays important roles in multiple cellular processes including cell growth/survival as well as metabolism.
Topics: Amino Acid Sequence; Catalytic Domain; Cell Survival; Humans; Lipid Metabolism; Lipids; PTEN Phosphohydrolase; Phosphorylation; Protein Structure, Tertiary; Signal Transduction
PubMed: 31548229
DOI: 10.1101/cshperspect.a036301 -
Biochimica Et Biophysica Acta.... Jan 2023Membrane proteins reside at interfaces between aqueous and lipid media and solving their molecular structure relies most of the time on removing them from the membrane... (Review)
Review
Membrane proteins reside at interfaces between aqueous and lipid media and solving their molecular structure relies most of the time on removing them from the membrane using detergent. Luckily, this solubilization process does not strip them from all the associated lipids and single-particle cryo-transmission electron microscopy (SP-TEM) has proved a very good tool to visualise both protein high-resolution structure and, often, many of its associated lipids. In this review, we observe membrane protein structures from the Protein DataBank and their associated maps in the Electron Microscopy DataBase and determine how the SP-TEM maps allow lipid visualization, the type of binding sites, the influence of symmetry, resolution and other factors. We illustrate lipid visualization around and inside the protein core, show that some lipid bilayers in the core can be shifted with respect to the membrane and how some proteins can actively bend the lipid bilayer that binds to them. We conclude that resolution improvement in SP-TEM will likely enable many more discoveries regarding the role of lipids bound to proteins.
Topics: Cryoelectron Microscopy; Membrane Proteins; Lipid Bilayers; Membranes; Molecular Structure
PubMed: 36216098
DOI: 10.1016/j.bbamem.2022.184068 -
The Journal of Membrane Biology Dec 2020Transmembrane substrate cleavage by the small Escherichia coli rhomboid protease GlpG informs on mechanisms by which lipid interactions shape reaction coordinates of... (Review)
Review
Transmembrane substrate cleavage by the small Escherichia coli rhomboid protease GlpG informs on mechanisms by which lipid interactions shape reaction coordinates of membrane-embedded enzymes. Here, I review and discuss new work on the molecular picture of protein-lipid interactions that might govern the formation of the substrate-enzyme complex in fluid lipid membranes. Negatively charged PG-type lipids are of particular interest, because they are a major component of bacterial membranes. Atomistic computer simulations indicate POPG and DOPG lipids bridge remote parts of GlpG and might pre-occupy the substrate-docking site. Inhibition of catalytic activity by PG lipids could arise from ligand-like lipid binding at the active site, which could delay or prevent substrate docking. Dynamic protein-lipid H-bond networks, water access to the active site, and fluctuations in the orientation of GlpG suggest that GlpG has lipid-coupled dynamics that could shape the energy landscape of transmembrane substrate docking.
Topics: Amino Acid Sequence; Binding Sites; Catalysis; Catalytic Domain; Hydrogen Bonding; Lipid Bilayers; Membrane Lipids; Membrane Proteins; Models, Molecular; Peptide Hydrolases; Phosphatidylglycerols; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 33210155
DOI: 10.1007/s00232-020-00152-z -
The New Phytologist Jul 2019Plant lipid signals are crucial developmental modulators and stress response mediators. A family of acyl-CoA-binding proteins (ACBPs) participates in the lipid... (Review)
Review
Plant lipid signals are crucial developmental modulators and stress response mediators. A family of acyl-CoA-binding proteins (ACBPs) participates in the lipid trafficking of these signals. Isoform-specific functions can arise from differences in their subcellular distribution, tissue-specificity, stress-responsiveness, and ligand selectivity. In lipid-mediated cell signaling, plant ACBPs are not merely transporters but are also important regulators via their interaction with lipid-metabolic enzymes and precursor lipids. In this Insight, the regulatory roles of plant ACBPs in the synthesis of various signaling lipids, including phosphatidic acid, sterols, oxylipins, and sphingolipids, are reviewed. We focus on the functional significance of these lipid signals in plant development and stress responses with an overview of recent work using reverse genetics and transgenic Arabidopsis.
Topics: Arabidopsis; Arabidopsis Proteins; Diazepam Binding Inhibitor; Lipids; Models, Biological; Signal Transduction
PubMed: 30676650
DOI: 10.1111/nph.15707