Lipid binding by fragments of apolipoprotein C-III-1 obtained by thrombin cleavage

Sparrow, James T.; Pownall, Henry J.; Hsu, Fu Juan; Blumenthal, Lee D.; Culwell, Alan R.; Gotto, Antonio M.

doi:10.1021/bi00644a004

Cited by 50 publications

(25 citation statements)

References 11 publications

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“…No secondary structure was induced in the N-terminal fragment when added to DMPC liposomes. In contrast, the ␣-helical content was increased in the C-terminal fragment, indicating lipid binding (60). In that study, only the C-terminal fragment was capable of inhibiting LPL activity, but the fragment was somewhat less potent when compared with the fulllength protein.…”

Section: Discussionmentioning

confidence: 75%

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Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Larsson

Vorrsjö

Talmud

et al. 2013

Journal of Biological Chemistry

147

128

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Background: Apolipoproteins (apo) C-I and C-III regulate plasma triglyceride metabolism by inhibition of lipoprotein lipase (LPL) activity. Results: ApoC-I or apoC-III prevents LPL from binding to lipid droplets. This results in inhibition of LPL. Conclusion: Inhibition of LPL activity by apoC-I and apoC-III is due to displacement of LPL from lipid droplets. Significance: Our proposed mechanism explains several effects of these apolipoproteins on lipoprotein metabolism.

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Section: Discussionmentioning

confidence: 75%

“…Previous studies had shown that cleavage of apoC-III by thrombin generates two fragments (residues 1-40 and 41-78) (60,61). No secondary structure was induced in the N-terminal fragment when added to DMPC liposomes.…”

Section: Discussionmentioning

confidence: 88%

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Larsson

Vorrsjö

Talmud

et al. 2013

Journal of Biological Chemistry

147

128

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“…Structure predictions have indicated that two amphipathic helices are likely to be formed (1,27). There is no consensus about which regions are most important for attachment to lipids (27)(28)(29). The structurally related apoCII is known to interact with LPL and activate this enzyme via the C-terminal helix (30), most likely in a dynamic fashion (23).…”

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confidence: 99%

Structure and Dynamics of Human Apolipoprotein CIII

Gangabadage

Zdunek

Tessari

et al. 2008

Journal of Biological Chemistry

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Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids (hypertriglyceridemia). Here, we report the three-dimensional NMR structure and dynamics of human apo-CIII in complex with SDS micelles, mimicking its natural lipidbound state. Thanks to residual dipolar coupling data, the first detailed view is obtained of the structure and dynamics of an intact apolipoprotein in its lipid-bound state. ApoCIII wraps around the micelle surface as a necklace of six ϳ10-residue amphipathic helices, which are curved and connected via semiflexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their three-dimensional conformation is similar to that of the low density lipoprotein receptor binding motifs of apoE/B and the receptor-associated protein. At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4 and 5 and the adjacent flexible loop. Sequence comparison shows that this asymmetric charge distribution along the solvent-exposed face of apoCIII as well as other structural features are conserved among mammals. This structure provides a template for exploration of molecular mechanisms by which human apoCIII inhibits lipoprotein lipase and receptor binding.Apolipoproteins consist of five major classes, apo-A 2 through -E, and several subclasses. They are designed for lipid transport in blood and are attached to lipid droplets (lipoproteins) through amphipathic helices that intercalate into the single layer of phospholipids and cholesterol covering the droplet (1-3). The apolipoproteins regulate blood lipid levels by interaction with specialized endocytotic receptors and by modulating enzyme activities and lipid exchange reactions (4). They are therefore in focus with regard to disturbances in blood lipid metabolism (dyslipidemias), which in turn are associated with metabolic disorders like obesity, insulin resistance, diabetes type 2, and cardiovascular disease.Apolipoprotein CIII (apoCIII) is the most abundant C-apolipoprotein in humans (2-4). It is found on very low density lipoproteins, chylomicrons, and high density lipoproteins (HDL). ApoCIII is predominantly expressed in liver and intestine from a gene cluster important for lipid regulation (ApoAI, -AIV, -AV, and -CIII) (4, 5). ApoCIII inhibits lipoprotein lipase (LPL) and receptor-mediated endocytosis of lipoprotein particles by competing for space at the surface of the lipoproteins and by interfering with their binding to endothelial proteoglycans and to specific lipoprotein receptors (2, 4, 6). Overexpression of apoCIII in transgenic mice leads to severely increased plasma triglyceride levels due to accumulation of very low density lipoprotein-like lipoprotein remnants w...

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“…A fundamental property is that the protein can bind rapidly and reversibly to lipoproteins. Sparrow et al [40] showed that the ability to bind to lipid resides in the C-terminal half of human apo CIII. Later Sparrow and Gotto [41] reported that fragment 49-80 bound to lipid, but that fragment 56-80 did not (residue numbers according to Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Based on theoretical and physical studies it is assumed that residues 41 -67 form an amphipathic helix on interaction with lipid [39]. In support of this, Sparrow et al [40] reported that when apo CIII was cleaved with thrombin, fragment 41 -79, but not fragment 1-40 bound to lipid. Furthermore, Sparrow and Gotto [41] reported that the synthetic fragments 41 -79 and 48 -79 bound to phospholipids, while the shorter fragments 55-79 and 61 -79 did not.…”

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confidence: 99%

Primary structure of the bovine analogues to human apolipoproteins CII and CIII

Bengtsson‐Olivecrona

Sletten

1990

European Journal of Biochemistry

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Two major isoforms of the bovine analogue to human apolipoprotein (apo) CII were purified from plasma. They were both as effective as human apo CII in activating lipoprotein lipase. Amino acid sequencing revealed that one form contained 79 amino acid residues, and corresponded to human pro apo CII. The other form lacked the first six residues at its N-terminus. This was apparently due to cleavage of the -Gln-Asp-linkage in the sequence H2N-Ala-His-Val-Pro-Gln-Gln-Asp-Glu-, analogous to cleavages described for human apo A1 and apo CII.Previous studies with human apo CII have shown that the ability to activate lipoprotein lipase resides in the C-terminal third of the molecule. This was highly conserved in the bovine analogue: of the 30 last residues, 21 are identical. Five residues in this part of human apo CII have been reported to be essential for activation of lipoprotein lipase. Only one of these, Tyr63, is present in the bovine sequence. The bovine structure contains a threonine at position 61, instead of serine in the human, and the four last residues are -Ser-Gly-Lys-Asp instead of the allegedly necessary -Lys-Gly-Glu-Glu. Three differently sialylated isoforms of the bovine analogue to human apolipoprotein CIII were also isolated and partially sequenced. All three lacked the first three N-terminal residues as compared to sequences from other species (man, dog and rat). Sequence differences were more pronounced at the ends than in the central parts of the apo CIII molecules.Transport of triacylglycerol in lipoproteins is a major pathway for energy transfer between tissues. Triacylglycerol-rich lipoproteins are formed in the intestine (chylomicra) and in the liver (very-low-density-lipoproteins). Their metabolism involves two major steps. Most of the triacylglycerols are unloaded by lipoprotein lipase at the vascular endothelium in peripheral tissues [ 11. The resulting remnant lipoproteins are then removed from the circulation mainly by the liver [2 -41. Apolipoproteins (apo) CII and CHI appear to be involved in the regulation of both steps. These proteins have flexible conformations [5] that allow them to bind reversibly to lipid/ water interfaces and to transfer rapidly between lipoprotein particles. When triacylglycerol-rich lipoproteins enter plasma they take up apo CII and CHI; when the particles are degraded by lipoprotein lipase the C apolipoproteins transfer back to other lipoproteins [6, 71. For hydrolysis by lipoprotein lipase the lipoproteins must carry apo CII, an activator for the enzyme [8, 91. In the absence of apo CII, triacylglycerol transport is severely impeded and gross hypertriglyceridemia ensues [lo]. Apo CIII has been shown to impede the interaction of lipoproteins with the remnant receptor, thus preventing their uptake by the liver until the lipase reaction has reduced them sufficiently in size so that most of the C apoproteins have been shed from the particles [4,11, 121. In addition, apo CIII has been shown to inhibit the action of lipoprotein lipase and the Human apo CII is a 79-a...

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Lipid binding by fragments of apolipoprotein C-III-1 obtained by thrombin cleavage

Cited by 50 publications

References 11 publications

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Structure and Dynamics of Human Apolipoprotein CIII

Primary structure of the bovine analogues to human apolipoproteins CII and CIII

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