Effect of bilayer membrane curvature on activity of phosphatidylcholine exchange protein

doi:10.1016/0005-2736(80)90355-7

Biochimica et Biophysica Acta (BBA) - Biomembranes

Volume 596, Issue 2, 28 February 1980, Pages 201-209

https://doi.org/10.1016/0005-2736(80)90355-7 Get rights and content

Abstract

Effect of bilayer membrane curvature of substrate phosphatidylcholine and inhibitor phosphatidylserine on the activity of phosphatidylcholine exchange protein has been studied by measuring transfer of spin-labeled phosphatidylcholine between vesicles, vesicles and liposomes, and between liposomes. The transfer rate between vesicles was more than 100 times larger than that between vesicles and liposomes. The transfer rate between liposomes was still smaller than that between vesicles and liposomes and nearly the same as that in the absence of exchange protein. The markedly enhanced exchange with vesicles was ascribed to the asymmetric packing of phospholipid molecules in the outer layer of the highly curved bilayer membrane. The inhibitory effect of phosphatidylserine was also greatly dependent on the membrane curvature. The vesicles with diameter of 17 nm showed more than 20 times larger inhibitory activity than those with diameter of 22 nm. The inhibitory effect of liposomes was very small. The size dependence was ascribed to stronger binding of the exchange protein to membranes with higher curvatures. The protein-mediated transfer from vesicles to spiculated erythrocyte ghosts was about four times faster than that to cup-shaped ghosts. This was ascribed to enhanced transfer to the highly curved spiculated membrane sites rather than greater mobility of phosphatidylcholine in the spiculated ghost membrane.

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Glycolipid transfer proteins (GLTPs) are small (24 kDa), soluble, ubiquitous proteins characterized by their ability to accelerate the intermembrane transfer of glycolipids in vitro. GLTP specificity encompasses both sphingoid- and glycerol-based glycolipids, but with a strict requirement that the initial sugar residue be beta-linked to the hydrophobic lipid backbone. The 3D architecture of GLTP reveals liganded structures with unique lipid-binding modes. The biochemical properties of GLTP action at the membrane surface have been studied rather comprehensively, but the biological role of GLTP remains enigmatic. What is clear is that GLTP differs distinctly from other known glycolipid-binding proteins, such as nonspecific lipid transfer proteins, lysosomal sphingolipid activator proteins, lectins, lung surfactant proteins as well as other lipid-binding/transfer proteins. Based on the unique conformational architecture that targets GLTP to membranes and enables glycolipid binding, GLTP is now considered the prototypical and founding member of a new protein superfamily in eukaryotes.
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The interaction of membranes with proteins can compensate for these effects. Several cases have been reported wherein increased membrane curvature or curvature strain promotes protein-membrane interactions (8, 9, 11, 56-61). Thus, the energy required for annexin B12 to interact with highly curved vesicles composed of cylindrical lipids (Figs. 2, 3, 4, 5 and 6), or with moderately curved vesicles containing lipids with negative curvature (Fig. 7), may be derived from stabilization of the curvature strain in these membranes.
The regulation of membrane curvature plays an important role in many membrane trafficking and fusion events. Recent studies have begun to identify some of the proteins involved in controlling and sensing the curvature of cellular membranes. A mechanistic understanding of these processes is limited, however, as structural information for the membrane-bound forms of these proteins is scarce. Here, we employed a combination of biochemical and biophysical approaches to study the interaction of annexin B12 with membranes of different curvatures. We observed selective and Ca²⁺-independent binding of annexin B12 to negatively charged vesicles that were either highly curved or that contained lipids with negative intrinsic curvature. This novel curvature-dependent membrane interaction induced major structural rearrangements in the protein and resulted in a backbone fold that was different from that of the well characterized Ca²⁺-dependent membrane-bound form of annexin B12. Following curvature-dependent membrane interaction, the protein retained a predominantly α-helical structure but EPR spectroscopy studies of nitroxide side chains placed at selected sites on annexin B12 showed that the protein underwent inside-out refolding that brought previously buried hydrophobic residues into contact with the membrane. These structural changes were reminiscent of those previously observed following Ca²⁺-independent interaction of annexins with membranes at mildly acidic pH, yet they occurred at neutral pH in the presence of curved membranes. The present data demonstrate that annexin B12 is a sensor of membrane curvature and that membrane curvature can trigger large scale conformational changes. We speculate that membrane curvature could be a physiological signal that induces the previously reported Ca²⁺-independent membrane interaction of annexins in vivo.
Glycolipid transfer protein interaction with bilayer vesicles: Modulation by changing lipid composition
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Essential for verification of this model and elimination of alternative models is direct monitoring of the location of GLTP with respect to the membrane. Although other models have been developed for phospholipid transfer proteins (38–43), these models traditionally rely on ordinary two-substrate enzyme-catalyzed reactions that can be adequately described by “ping-pong Bi-Bi” mechanisms. The models are well suited for describing transfer mechanisms involving single component lipid membranes, as is the case for phosphatidylcholine transfer protein (38).
Glycosphingolipids (GSLs) are important constituents of lipid rafts and caveolae, are essential for the normal development of cells, and are adhesion sites for various infectious agents. One strategy for modulating GSL composition in lipid rafts is to selectively transfer GSL to or from these putative membrane microdomains. Glycolipid transfer protein (GLTP) catalyzes selective intermembrane transfer of GSLs. To enable effective use of GLTP as a tool to modify the glycolipid content of membranes, it is imperative to understand how the membrane regulates GLTP action. In this study, GLTP partitioning to membranes was analyzed by monitoring the fluorescence resonance energy transfer from tryptophans and tyrosines of GLTP to N-(5-dimethyl-aminonaphthalene-1-sulfonyl)-1,2-dihexadecanoyl-sn-glycero-3-phospho-ethanolamine present in bilayer vesicles. GLTP partitioned to POPC vesicles even when no GSL was present. GLTP interaction with model membranes was nonpenetrating, as assessed by protein-induced changes in lipid monolayer surface pressure, and nonperturbing in that neither membrane fluidity nor order were affected, as monitored by anisotropy of 1,6-diphenyl-1,3,5-hexatriene and 6-dodecanoyl-N,N-dimethyl-2-naphthylamine, even though the tryptophan anisotropy of GLTP increased in the presence of vesicles. Ionic strength, vesicle packing, and vesicle lipid composition affected GLTP partitioning to the membrane and led to the following conclusion: Conditions that increase the ratio of bound/unbound GLTP do not guarantee increased transfer activity, but conditions that decrease the ratio of bound/unbound GLTP always diminish transfer. A model of GLTP interaction with the membrane, based on the partitioning equilibrium data and consistent with the kinetics of GSL transfer, is presented and solved mathematically.
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An independent filtration binding assay confirmed these results, demonstrating that NSP4 and NSP4114–135 interact exclusively with lipids and preferentially interact with vesicles that are highly curved, rich in anionic phospholipids and cholesterol, and thus resemble caveolae microdomains (Anderson et al., 1992; Brown and Rose, 1992; Rothberg et al., 1992; Anderson, 1998). The structural basis of NSP4, SCP-2, and corresponding synthetic peptide interactions with highly curved membranes likely includes the more mobile packing and lower surface pressure of the phospholipids in the outer leaflet and the packing constraint in the inner leaflet (Machida and Ohnishi, 1980; Talbot et al., 1997), resulting in an exposed hydrophobic core that may facilitate hydrophobic interactions. Highly curved membrane regions are prevalent in the intestinal microvillus (Lipka et al., 1995; Boffelli et al., 1997), the site of NSP4 enterotoxic activity (Chan et al., 1988).
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Translocations of various lipid species between membranes have been extensively studied. The transport of water-insoluble lipids is thought to require the participation of lipid transfer proteins (LTP). Several LTP, differing in their physicochemical properties and substrate specificities, have been purified to homogeneity from blood plasma, eucaryotic and procaryotic cells. Depending on their site of activity, they can be classified as extracellular and intracellular LTP. Extracellular LTP are found in the blood plasma and intracellular LTP, which were originally characterized as phospholipid exchange proteins, are ubiquitous in nature. Despite the enormous knowledge about their physicochemical properties and their function in vitro their physiological role has not been clearly demonstrated. However, their ubiquitous occurrence indicates an important role in cellular events. This review gives an overview of this interesting category of proteins, which are able to catalyze inter-membrane transfer and exchange of lipids.

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Effect of bilayer membrane curvature on activity of phosphatidylcholine exchange protein

Abstract

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

FEBS Lett.

Biochim. Biophys. Acta

Methods Enzymol.

J. Biol. Chem.

Biochim. Biophys. Acta

Blood

Chem. Phys. Lipids

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

Biochemistry