The Hydrophobic Face Orientation of Apolipoprotein A-I Amphipathic Helix Domain 143–164 Regulates Lecithin:Cholesterol Acyltransferase Activation

Sorci‐Thomas, Mary G.; Curtiss, Linda K.; Parks, John S.; Thomas, Michael J.; Kearns, Mary; Landrum, Mark

doi:10.1074/jbc.273.19.11776

Cited by 71 publications

(73 citation statements)

References 45 publications

(45 reference statements)

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“…Biochemical Characterization-ApoA-I acts as a cofactor for LCAT, and repeat 6 (residues 143-164) is thought to regulate this process (36,37), although residues 99 -120 (containing Met 112 ) may also participate (38). As can be seen in Table IV, the ability of drHDL A-I and drHDL A-Iϩ32 to activate LCAT was comparable.…”

Section: Resultsmentioning

confidence: 99%

Oxidation of Methionine Residues to Methionine Sulfoxides Does Not Decrease Potential Antiatherogenic Properties of Apolipoprotein A-I

Panzenboeck¹,

Kritharides²,

Raftery³

et al. 2000

Journal of Biological Chemistry

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The initial stage of oxidation of high density lipoproteins (HDL) is accompanied by the lipid hydroperoxidedependent, selective oxidation of two of the three Met residues of apolipoprotein A-I (apoA-I) to Met sulfoxides (Met(O)). Formation of such selectively oxidized apoA-I (i.e. apoA-I ؉32 ) may affect the antiatherogenic properties of HDL, because it has been suggested that Met 86 and Met 112 are important for cholesterol efflux and Met 148 is involved in the activation of lecithin:cholesterol acyl transferase (LCAT). We therefore determined which Met residues were oxidized in apoA-I ؉32 and how such oxidation of apoA-I affects its secondary structure, the affinity for lipids, and its ability to remove lipids from human macrophages. We also assessed the capacity of discoidal reconstituted HDL containing apoA-I ؉32 to act as substrate for LCAT, and the dissociation of apoA-I and apoA-I ؉32 from reconstituted HDL. Met 86 and Met 112 were present as Met(O), as determined by amino acid sequencing and mass spectrometry of isolated peptides derived from apoA-I ؉32 . Selective oxidation did not alter the ␣-helicity of lipid-free and lipid-associated apoA-I as assessed by circular dichroism, and the affinity for LCAT was comparable for reconstituted HDL containing apoA-I or apoA-I ؉32 . Cholesteryl ester transfer protein mediated the dissociation of apoA-I more readily from reconstituted HDL containing apoA-I ؉32 than unoxidized apoA-I. Also, compared with native apoA-I, apoA-I ؉32 had a 2-to 3-fold greater affinity for lipid (as determined by the rate of clearance of multilamellar phospholipid vesicles) and its ability to cause efflux of [ 3 H]cholesterol, [ 3 H]phospholipid, and [ 14 C]␣-tocopherol from lipid-laden human monocyte-derived macrophages was significantly enhanced. By contrast, no difference was observed for cholesterol and ␣-tocopherol efflux to lipid-associated apolipoproteins. Together, these results suggest that selective oxidation of Met residues enhances rather than diminishes known antiatherogenic activities of apoA-I, consistent with the overall hypothesis that detoxification of lipid hydroperoxides by HDL is potentially antiatherogenic.

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Section: Resultsmentioning

confidence: 99%

Oxidation of Methionine Residues to Methionine Sulfoxides Does Not Decrease Potential Antiatherogenic Properties of Apolipoprotein A-I

Panzenboeck¹,

Kritharides²,

Raftery³

et al. 2000

Journal of Biological Chemistry

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“…We observed that both His-⌬1-43 and His-⌬1-65 apoA-I were associated with decreases in LCAT activation relative to His-Wt apoA-I (Table II). The observation that these deletions affected LCAT activation is intriguing, because this property is generally associated with class A helices of the central domain, in particular helix 6 (29,46,47). Recent work suggests that a cluster of 3 arginine Arg residues at the interface of the hydrophilic and hydrophobic faces in helix 6 contributes to a specific locale of positive surface potential that may stimulate LCAT activity (48).…”

Section: The N Terminus Of Apoa-i Is Essential For Hdl Maturationmentioning

confidence: 99%

The N-terminal Globular Domain and the First Class A Amphipathic Helix of Apolipoprotein A-I Are Important for Lecithin:Cholesterol Acyltransferase Activation and the Maturation of High Density Lipoprotein in Vivo

Scott¹,

McManus²,

Franklin³

et al. 2001

Journal of Biological Chemistry

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To investigate the role of the N terminus of apolipoprotein A-I (apoA-I) in the maturation of high density lipoproteins (HDL), two N-terminal mutants with deletions of residues 1-43 and 1-65 (referred to as ⌬1-43 and ⌬1-65 apoA-I) were studied. In vitro, these deletions had little effect on cellular cholesterol efflux from macrophages but LCAT activation was reduced by 50 and 70% for the ⌬1-43 and ⌬1-65 apoA-I mutants, respectively, relative to wild-type (Wt) apoA-I. To further define the role of the N terminus of apoA-I in HDL maturation, we constructed recombinant adenoviruses containing Wt apoA-I and two similar mutants with deletions of residues 7-43 and 7-65 (referred to as ⌬7-43 and ⌬7-65 apoA-I, respectively). Residues 1-6 were not removed in these mutants to allow proper cleavage of the pro-sequence in vivo. Following injection of these adenoviruses into apoA-I-deficient mice, plasma concentrations of both ⌬7-43 and ⌬7-65 apoA-I were reduced 4-fold relative to Wt apoA-I. The N-terminal deletion mutants, in particular ⌬7-65 apoA-I, were associated with greater proportions of pre␤-HDL and accumulated fewer HDL cholesteryl esters relative to Wt apoA-I. Wt and ⌬7-43 apoA-I formed predominantly ␣-migrating and spherical HDL, whereas ⌬7-65 apoA-I formed only pre␤-HDL of discoidal morphology. This demonstrates that deletion of the first class A amphipathic ␣-helix has a profound additive effect in vivo over the deletion of the globular domain alone (amino acids 1-43) indicating its important role in the production of mature ␣-migrating HDL. In summary, the combined in vitro and in vivo studies demonstrate a role for the N terminus of apoA-I in lecithin:cholesterol acyltransferase activation and the requirement of the first class A amphipathic ␣-helix for the maturation of HDL in vivo. High density lipoproteins (HDL)1 transport cholesterol from peripheral tissues to the liver in a process known as reverse cholesterol transport (1). This pathway is accepted as a primary mechanism by which HDL exert their anti-atherogenic effects. Nascent HDL are secreted by hepatocytes, liberated from chylomicrons during triglyceride lipolysis, and are derived from HDL remodeling by hepatic lipase and cholesteryl ester transfer protein. The importance of phospholipid transfer protein (PLTP) in the lipidation of this nascent HDL pool has recently emerged, because PLTP-deficient mice exhibit defective phospholipid transfer from triglyceride-rich lipoproteins to HDL, reduced HDL levels, and increased HDL catabolism (2). Efflux of cholesterol and phospholipids from cells provide nascent HDL with lipid constituents. This step is important for steady-state concentrations of HDL, because efflux is a ratelimiting step in HDL maturation as heterozygous mutations in the ATP binding cassette transporter A1 (ABCA1) can cause familial HDL deficiency (3). The combined actions of PLTP and ABCA1 generate larger discoidal pre␤ 2 and pre␤ 3 -HDL from the nascent HDL pool, which are converted to spherical ␣-migrating HDL by the actions of lecithin:...

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“…LCAT activation [6]. The C-terminal part of apo A-I was shown to be responsible for association with lipids [7], whereas the Nterminal part seems to be responsible for stabilizing its lipid-free structure [8,9].…”

Section: Ormentioning

confidence: 99%

Reagent or myeloperoxidase-generated hypochlorite affects discrete regions in lipid-free and lipid-associated human apolipoprotein A-I

Bergt

OETTL²,

Keller

et al. 2000

Biochem. J.

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The Hydrophobic Face Orientation of Apolipoprotein A-I Amphipathic Helix Domain 143–164 Regulates Lecithin:Cholesterol Acyltransferase Activation

Cited by 71 publications

References 45 publications

Oxidation of Methionine Residues to Methionine Sulfoxides Does Not Decrease Potential Antiatherogenic Properties of Apolipoprotein A-I

Oxidation of Methionine Residues to Methionine Sulfoxides Does Not Decrease Potential Antiatherogenic Properties of Apolipoprotein A-I

The N-terminal Globular Domain and the First Class A Amphipathic Helix of Apolipoprotein A-I Are Important for Lecithin:Cholesterol Acyltransferase Activation and the Maturation of High Density Lipoprotein in Vivo

Reagent or myeloperoxidase-generated hypochlorite affects discrete regions in lipid-free and lipid-associated human apolipoprotein A-I

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