Binding Steps of Apolipoprotein A-I with Phospholipid Monolayers:  Adsorption and Penetration

Lecompte, M.F.; Bras, Anne-Claire; Dousset, N.; Portas, Isabelle; Salvayre, Robert; Ayrault-Jarrier, M

doi:10.1021/bi9813072

Cited by 56 publications

(50 citation statements)

References 35 publications

(61 reference statements)

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“…The surface of natural chylomicrons and VLDL is stabilized by amphophilic apolipoproteins, mainly apolipoprotein B-48 for chylomicrons and apolipoproteins B-100 and E for VLDL, and apolipoproteins are the main plasma proteins that interact with PEGylated solid lipid nanoparticles (32,33). Apolipoprotein AI efficiently binds and eventually enters phospholipid monolayers (34,35). Coating with blood proteins is a promiscuous factor controlling the pharmacokinetics of nanoparticles (21,36).…”

Section: Discussionmentioning

confidence: 99%

Synthetic Lipid Nanoparticles Targeting Steroid Organs

et al. 2013

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Lipidots are original nanoparticulate lipid delivery vectors for drugs and contrast agents made from materials generally regarded as safe. Here, we characterized the in vivo stability, biodistribution, and pharmacokinetics of lipidots. Methods: Lipidots 55 nm in diameter and coated with a phospholipid/poly(ethyleneglycol) surfactant shell were triply labeled with 3 H-cholesteryl-hexadecyl-ether, cholesteryl-14 C-oleate, and the 1,19-dioctadecyl-3,3,39,39-tetramethylindotricarbocyanine infrared fluorescent dye and injected intravenously into immunocompetent Friend virus B-type mice. The pharmacokinetics and biodistribution of lipidots were analyzed quantitatively in serial samples of blood and tissue and with in vivo optical imaging and were refined by microscopic examination of selected target tissues. Results: The plasmatic half-life of lipidots was approximately 30 min. Radioactive and fluorescent tracers displayed a similar nanoparticle-driven biodistribution, indicative of the lipidots' integrity during the first hours after injection. Lipidots distributed in the liver and, surprisingly, in the steroid-rich organs adrenals and ovaries, but not in the spleen. This tropism was confirmed at the microscopic level by histologic detection of 1,19-dioctadecyl-3,3,39,39-tetramethylindotricarbocyanine. Nanoparticle loading with cholesterol derivatives increased accumulation in ovaries in a dosedependent manner. Conclusion: This previously unreported distribution pattern is specific to lipidots and attributed to their nanometric size and composition, conferring on them a lipoproteinlike behavior. The affinity of lipidots for steroid hormone-rich areas is of interest to address drugs and contrast agents to lipoprotein-receptor-overexpressing cancer cells found in hormone-dependent tumors.

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Section: Discussionmentioning

confidence: 99%

Synthetic Lipid Nanoparticles Targeting Steroid Organs

et al. 2013

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“…Both the vesicle binding and the monolayer penetration of the C1 domain require, however, the presence of anionic phospholipids, indicating that nonspecific electrostatic interactions are a driving force for its initial membrane binding. A recent monolayer study has shown that the monolayer penetration of surface active proteins, such as apolipoproteins, follows a two-step mechanism in which electrostatic surface adsorption precedes the insertion of hydrophobic side chains into the hydrophobic moiety of the monolayer (45). Based on the tertiary structure and monolayer penetration properties of the isolated C1 domain, it appears that the membrane penetration of the C1 domain follows a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

Interplay of C1 and C2 Domains of Protein Kinase C-α in Its Membrane Binding and Activation

Medkova

Cho

1999

Journal of Biological Chemistry

157

184

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The regulatory domain of conventional protein kinase C (PKC) contains two membrane-targeting modules, the C2 domain that is responsible for Ca 2؉ -dependent membrane binding of protein, and the C1 domain composed of two cysteine-rich zinc fingers (C1a and C1b) that bind diacylglycerols and phorbol esters. To understand the individual roles and the interplay of the C1 and C2 domains in the membrane binding and activation of PKC, we functionally expressed isolated C1 and C2 domains of PKC-␣ and measured their vesicle binding and monolayer penetration. Results indicate that the C2 domain of PKC-␣ is responsible for the initial Ca 2؉ -and phosphatidylserine-dependent electrostatic membrane binding of PKC-␣, whereas the C1 domain is involved in subsequent membrane penetration and diacylglycerol binding, which eventually lead to enzyme activation. To determine the roles of individual zinc fingers in the C1 domain, we also mutated hydrophobic residues in the C1a (Trp 58 and Protein kinases C (PKCs)1 are a family of serine/threonine kinases that transduce the myriad of signals activating cellular functions and proliferation (1, 2). More than 10 members of the PKC family have been identified by molecular cloning. All PKCs contain an amino-terminal regulatory domain and a carboxyl-terminal catalytic domain. Based on structural differences in the regulatory domain, PKCs are generally classified into three groups; conventional PKC (␣, ␤I, ␤II, and ␥ subtypes), novel PKC (␦, ⑀, , and subtypes), and atypical PKC ( and subtypes). The regulatory domain of conventional PKCs is composed of two conserved membrane-targeting modules, C1 and C2 domains, as well as a pseudosubstrate region and variable regions. Conventional PKCs are activated by the Ca 2ϩ -dependent translocation of proteins to the membrane containing phosphatidylserine (PS) and diacylglycerol (DAG). Structural (3) and mutational (4, 5) studies have shown that the C2 domain of conventional PKC is responsible for the Ca 2ϩ -dependent translocation of the protein to membranes. It has also been shown that the C1 domain, which is composed of a tandem repeat of cysteine-rich zinc-finger domains (C1a and C1b), is involved in binding of PKC to DAG and its structural analogs, phorbol esters (6 -8). However, the temporal and spatial sequences of membrane targeting and activation of PKC have not been fully elucidated. Furthermore, the interplay of the C1 and C2 domains in these complex processes is poorly understood. Finally, the roles of individual zinc finger domains in the DAGdependent membrane binding and activation of PKC are not well defined. To address these questions, we functionally expressed the isolated C1 and C2 domains of PKC-␣ and measured their vesicle binding and monolayer penetration. We also mutated C1a and C1b domain residues of the native PKC-␣ and measured the effects of mutations on vesicle binding, enzyme activity, and monolayer penetration. Results indicate that the C2 domain of PKC-␣ is responsible for its initial Ca 2ϩ -and PS-dependent membrane bind...

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“…It is also possible that the phospholipid head groups can bend slightly around the sides of the helices to interact with negative charges along the polar surface of the helix, shortening the effective distance that the protein needs to cover. Such phospholipid to amphipathic helix interactions have been proposed to occur on the surface of spherical HDL particles or vesicles (36,37).…”

Section: Discussionmentioning

confidence: 99%

The Orientation of Helix 4 in Apolipoprotein A-I-containing Reconstituted High Density Lipoproteins

Maiorano

Davidson

2000

Journal of Biological Chemistry

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The three-dimensional structure of the high density lipoprotein (HDL) component apolipoprotein (apo) A-I and the molecular basis for its protection against coronary artery disease are unknown. In terms of discoidal HDL particles, there has been a debate as to the orientation of the apoA-I ␣-helices around the disc edge. The "picket fence" model states that the ␣-helical repeats, separated by turns, are arranged parallel to the phospholipid acyl chains of the enclosed lipid bilayer. On the other hand, the "belt" model states that the helical segments run perpendicular to the acyl chains. To distinguish between these models, we used nitroxide spin labels present at various depths in the bilayer of reconstituted HDL (rHDL) to measure the position of Trp residues in single Trp mutants of human proapoA-I. Two mutants were studied; the first contained a Trp at position 108, which was located near the center of helix 4. The second contained a Trp at position 115, two turns along the same helix. The picket fence model predicts that these Trp residues should be at different depths in the bilayer, whereas the belt model predicts that they should be at similar depths. Different sized rHDL particles were produced that contained 2, 3, and >4 molecules of proapoA-I per complex. In each case, parallax analysis indicated that Trp-108 and Trp-115 were present at similar depths of about 6 Å from the center of the bilayer, consistent with helix 4 being oriented perpendicular to the acyl chains (in agreement with the belt model). Similar experiments showed that control transmembrane peptides were oriented parallel to the acyl chains in vesicles, demonstrating that the method was capable of distinguishing between the two models. This study provides one of the first experimental measurements of the location of an apoA-I helix with respect to the bilayer edge.

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Binding Steps of Apolipoprotein A-I with Phospholipid Monolayers: Adsorption and Penetration

Cited by 56 publications

References 35 publications

Synthetic Lipid Nanoparticles Targeting Steroid Organs

Synthetic Lipid Nanoparticles Targeting Steroid Organs

Interplay of C1 and C2 Domains of Protein Kinase C-α in Its Membrane Binding and Activation

The Orientation of Helix 4 in Apolipoprotein A-I-containing Reconstituted High Density Lipoproteins

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