Anionic phospholipids, interfacial binding and the regulation of cell functions

Buckland, Andrew G.; Wilton, David C.

doi:10.1016/s1388-1981(99)00188-2

Cited by 110 publications

(93 citation statements)

References 160 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With regard to lipid headgroups, zwitterionic PC is the most abundant phospholipid in human cell membranes and PS is the most common anionic phospholipid, localized in the inner leaflet of cell membranes. 32−34 Furthermore, CL is a major component of the mitochondrial membrane 33 and carries two anionic phosphatidyl residues connected by a glycerol bridge and four acyl chains. Mitochondria have recently attracted interest as potential actors in the pathogenesis of PD.…”

mentioning

confidence: 99%

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Hellstrand

Grey

Ainalem

et al. 2013

ACS Chem. Neurosci.

102

View full text Add to dashboard Cite

An amyloid form of the protein α-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson's disease (PD). α-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating α-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric α-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniquesquartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that α-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of α-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of α-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.

show abstract

mentioning

confidence: 99%

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Hellstrand

Grey

Ainalem

et al. 2013

ACS Chem. Neurosci.

102

View full text Add to dashboard Cite

show abstract

“…Proteins that interact reversibly with cell membrane lipids usually have selectivity for negatively charged phospholipids (1,2). Some of these proteins show specificity for a particular anionic phospholipid.…”

mentioning

confidence: 99%

“…CTP:phosphocholine cytidylyltransferase (CT) 1 catalyzes a key rate-limiting step in PC synthesis and contributes to maintenance of cell membrane PC homeostasis (12). When the relative membrane PC content is altered, CT could respond by recognition of ensuing changes in the physical features of PCdeficient or PC-overloaded membranes, including changes in the negative surface charge density (13).…”

mentioning

confidence: 99%

Both Acidic and Basic Amino Acids in an Amphitropic Enzyme, CTP:Phosphocholine Cytidylyltransferase, Dictate Its Selectivity for Anionic Membranes

Johnson

Xie

Singh

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Amphitropic proteins are regulated by reversible membrane interaction. Anionic phospholipids generally promote membrane binding of such proteins via electrostatics between the negatively charged lipid headgroups and clusters of basic groups on the proteins. In this study of one amphitropic protein, a cytidylyltransferase (CT) that regulates phosphatidylcholine synthesis, we found that substitution of lysines to glutamine along both interfacial strips of the membrane-binding amphipathic helix eliminated electrostatic binding. Unexpectedly, three glutamates also participate in the selectivity for anionic membrane surfaces. These glutamates become protonated in the low pH milieu at the surface of anionic, but not zwitterionic membranes, increasing protein positive charge and hydrophobicity. The binding and insertion into lipid vesicles of a synthetic peptide containing the three glutamates was pHdependent with an apparent pK a that varied with anionic lipid content. Glutamate to glutamine substitution eliminated the pH dependence of the membrane interaction, and reduced anionic membrane selectivity of both the peptide and the whole CT enzyme examined in cells. Thus anionic lipids, working via surface-localized pH effects, can promote membrane binding by modifying protein charge and hydrophobicity, and this novel mechanism contributes to the membrane selectivity of CT in vivo.

show abstract

“…For example, a wide range of antimicrobial peptides bind to the anionic bacterial membrane, whereas binding to the zwitterionic eukaryotic cell membrane is minimal (12). The binding of cytochrome c to anionic phospholipids is an extensively studied model system (13,14), and the physiological importance of proteins binding to anionic interfaces has been reviewed (15). Thus, the interaction of liver FABP with anionic vesicles with accompanying ligand release provides another important model for such studies involving, in this case, a ␤-barrel structure.…”

mentioning

confidence: 99%

Effect of Charge Reversal Mutations on the Ligand- and Membrane-binding Properties of Liver Fatty Acid-binding Protein

Davies

Hagan

Wilton

2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

. Using a strategy of charge reversal mutagenesis, the potential role of specific cationic residues in promoting interfacial binding of FABP to anionic phospholipid vesicles has been investigated. Cationic residues chosen included those within the ␣-helical region (Lys-20, Lys-31, and Lys-33) and those that make a significant contribution to the positive surface potential of the protein (Lys-31, Lys-36, Lys-47, Lys-57, and Arg-126). Only three cationic residues make a significant contribution to interfacial binding, and these residues (Lys-31, Lys-36, and Lys-57) are all located within the ligand portal region, where the protein may be predicted to exhibit maximum disorder. The binding of tryptophan mutants, F3W, F18W, and C69W, to dioleoylphosphatidylglycerol vesicles, containing 5 mol% of the fluorescent phospholipid dansyldihexadecanoylphosphatidylethanolamine, was monitored by fluorescence resonance energy transfer (FRET). All three mutants showed enhanced dansyl fluorescence due to FRET on addition of phospholipid to protein; however, this fluorescence was considerably greater with the F3W mutant, consistent with the Nterminal region of the protein coming in close proximity to the phospholipid interface. These results were confirmed by succinimide quenching studies. Overall, the results indicate that the portal region of liver FABP and specifically Lys-31, Lys-36, and Lys-57 are involved in the interaction with the interface of anionic vesicles and that the N-terminal region of the protein undergoes a conformational change, resulting in DAUDA release.Liver fatty acid-binding protein (FABP) 1 is a member of a family of structurally related small (14 -15 kDa) cytosolic lipid binding proteins that also include intestinal, heart (muscle), adipocyte, ileal, keratinocyte, and brain FABP (for recent reviews, see Refs. 1-6). The exact physiological functions of these proteins are unclear, although it is generally thought that they may have a potential role in the uptake and targeting of fatty acids to various intracellular organelles and metabolic pathways. All further sites of metabolism of long chain fatty acids in the cell involve membrane proteins. For a targeting role to operate, the FABP must interact with an intracellular structure such as a membrane interface or receptor/docking protein.A process involving membrane binding has been advocated for intestinal, muscle, and adipose FABP where model fluorescence studies have led to the proposal of a collisional mechanism for explaining the FABP-mediated transfer of fatty acids between phospholipid membranes and vesicles (reviewed in Ref. 3). However, such a process was not observed to operate for liver FABP under the same assay conditions, and an aqueous phase diffusion mechanism is proposed, not requiring interaction of the protein with membrane surfaces (3). In contrast, using different assay conditions we have reported the apparent binding of liver FABP to anionic vesicles, monitored as the release of the fluorescent fatty acid ligand (DAUDA) from the protei...

show abstract

Anionic phospholipids, interfacial binding and the regulation of cell functions

Cited by 110 publications

References 160 publications

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Both Acidic and Basic Amino Acids in an Amphitropic Enzyme, CTP:Phosphocholine Cytidylyltransferase, Dictate Its Selectivity for Anionic Membranes

Effect of Charge Reversal Mutations on the Ligand- and Membrane-binding Properties of Liver Fatty Acid-binding Protein

Contact Info

Product

Resources

About