Disruption of the C-terminal helix by single amino acid deletion is directly responsible for impaired cholesterol efflux ability of apolipoprotein A-I Nichinan

Kono, Momoe; Tanaka, Toshitaka; Tanaka, Masafumi; Vedhachalam, Charulatha; Chetty, Palaniappan Sevugan; Nguyen, David; Dhanasekaran, Padmaja; Lund‐Katz, Sissel; Phillips, Michael C.; Saito, Hiroyuki

doi:10.1194/jlr.m002113

Cited by 21 publications

(26 citation statements)

References 57 publications

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“…We previously proposed that the stabilizing function of the N terminus is mediated by direct contact between ␤-strands found in the N-terminal (42) and C-terminal (31) domains. This direct contact between the N-and C-terminal domains (31,(47)(48)(49) is also thought to modulate the lipid-binding properties of the N terminus (50,51). Moreover, although naturally occurring mutations in the central domain of human apoA-I are typically associated with low plasma HDL concentrations and abolished lecithin:cholesterol acyltransferase activation, mutations in the N-terminal domain have a preponderance of amyloidogenic activity (for a review see Ref.…”

Section: Discussionmentioning

confidence: 99%

Structure of Apolipoprotein A-I N Terminus on Nascent High Density Lipoproteins

Lagerstedt

Cavigiolio²,

Budamagunta

et al. 2011

Journal of Biological Chemistry

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Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and a critical element of cholesterol metabolism. To better elucidate the role of the apoA-I structure-function in cholesterol metabolism, the conformation of the apoA-I N terminus (residues 6 -98) on nascent HDL was examined by electron paramagnetic resonance (EPR) spectroscopic analysis. A series of 93 apoA-I variants bearing single nitroxide spin label at positions 6 -98 was reconstituted onto 9.6-nm HDL particles (rHDL). These particles were subjected to EPR spectral analysis, measuring regional flexibility and side chain solvent accessibility. Secondary structure was elucidated from side-chain mobility and molecular accessibility, wherein two major ␣-helical domains were localized to residues 6 -34 and 50 -98. We identified an unstructured segment (residues 35-39) and a ␤-strand (residues 40 -49) between the two helices. Residues 14, 19, 34, 37, 41, and 58 were examined by EPR on 7.8, 8.4, and 9.6 nm rHDL to assess the effect of particle size on the N-terminal structure. Residues 14, 19, and 58 showed no significant rHDL size-dependent spectral or accessibility differences, whereas residues 34, 37, and 41 displayed moderate spectral changes along with substantial rHDL size-dependent differences in molecular accessibility. We have elucidated the secondary structure of the N-terminal domain of apoA-I on 9.6 nm rHDL (residues 6 -98) and identified residues in this region that are affected by particle size. We conclude that the inter-helical segment (residues 35-49) plays a role in the adaptation of apoA-I to the particle size of HDL.

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Section: Discussionmentioning

confidence: 99%

Structure of Apolipoprotein A-I N Terminus on Nascent High Density Lipoproteins

Lagerstedt

Cavigiolio²,

Budamagunta

et al. 2011

Journal of Biological Chemistry

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“…Mutations in helix 10 of human ApoA-I have been shown to decrease the rate of clearance of phospholipid in solution and the effl ux rate of cholesterol from cultured macrophages ( 14 ). The Nichinan variant of human ApoA-I lacks E235 in helix 10 and is associated with decreased ABCA1-mediated cholesterol effl ux from macrophages and decreased plasma HDL levels ( 15 ). It has been shown that the tertiary structure of lipid-free human ApoA-I is made up of two domains: an N-terminal ␣ -helix bundle from residues 1-187 (through helix 7) and a Cterminal less organized region (helices 8-10), which is the major lipid-binding region of the molecule ( 16,17 ).…”

Section: Proteomic Analysis Of the Hdl Particlesmentioning

confidence: 99%

Naturally occurring variant of mouse apolipoprotein A-I alters the lipid and HDL association properties of the protein

Sontag

Carnemolla

Vaisar

et al. 2012

Journal of Lipid Research

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is a major contributor to cardiovascular disease development ( 2 ). Although not fully understood, plasma lipoproteins play an important role in atherosclerosis, with plasma HDL cholesterol levels being inversely correlated with risk of cardiovascular disease ( 3 ). Much of our current knowledge of atherosclerosis comes from the use of atherosclerosis-susceptible animal models and particularly mouse models. Numerous inbred mouse strains display varying degrees of susceptibility to atherosclerotic lesion development, although the causes of these differences are unclear ( 4 ). Because wild-type (WT) mice do not develop atherosclerotic lesions, these comparisons were made using mice fed a cholate-containing diet high in fat and cholesterol in order to induce lesion formation. However, this diet also induces an infl ammatory response. Since then, several studies have shown further strain differences in atherosclerosis susceptibility in apolipoprotein (Apo)E and LDL-receptor knockout mice, the most commonly used genetic models of atherosclerosis ( 5, 6 ). Most atherosclerosis studies have been performed in the C57BL/6 (C57) strain, which appears to be the most sensitive of the mouse strains. Thus, in both genetic models, the C57BL/6 mouse strain develops lesions more than 5-fold greater in size than the atherosclerosis-resistant FVB/NJ (FVB) strain. These two mouse strains also differ in lipoprotein levels. In WT, ApoE, and LDL-receptor knockout mice, the FVB strain displays 2-fold higher levels of plasma HDL cholesterol ( 5, 6 ). The same is true in numerous other atherosclerosis-resistant strains ( 7 ). The genetic basis of increased HDL cholesterol and the resulting impact on atherosclerosis susceptibility in these mouse strains is not completely understood.

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“…DMPC-MLV were produced as described (57). The DMPC-MLV suspension (1 ml) was placed in a 1-cm path length quartz cell and equilibrated at 25°C for 5-10 min, during which the turbidity was recorded at 325 nm with an averaging time of 5 s as described (45). No significant changes in turbidity were detected during equilibration.…”

Section: Generation Expression and Purification Of Protein Variants-mentioning

confidence: 99%

“…ApoA-I Nichinan, a C-terminal single amino acid deletion variant (⌬E235) that associates with low plasma HDL levels and abnormal distribution of HDL subspecies, is another case of potentially self-association-dependent alteration of apoA-I functionality. In fact, the higher than wild-type self-association levels of apoA-I Nichinan may play a role in the lower lipidbinding and ABCA1-mediated cholesterol release efficiencies, leading to the dysfunctional HDL phenotype of Nichinan variant carriers (45).…”

mentioning

confidence: 99%

“…Importantly, increasing evidence suggest that dysfunctional apoA-Is, either by natural mutations (44,45) or by oxidative modifications (46), correspond to an altered self-association state that may contribute to the mechanism underlying protein malfunctioning. Recently, the heterozygous apoA-I S36A mutation has been linked to severe reduction in plasma pre-␤-HDL levels and a modified self-association state of the lipid-free protein, which has been proposed to contribute to the inability of the protein variant to produce a normal HDL phenotype (44).…”

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confidence: 99%

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Impact of Self-association on Function of Apolipoprotein A-I

Jayaraman

Abe-Dohmae

Yokoyama

et al. 2011

Journal of Biological Chemistry

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Background: Self-association is an intrinsic property of exchangeable apolipoproteins but an under-explored feature of the major protein of good cholesterol, apolipoprotein A-I. Result: Different degrees of apolipoprotein A-I self-association exhibit distinct in vitro lipid remodeling and cellular lipid release efficiencies. Conclusion: Self-association of apolipoprotein A-I modulates the biogenesis of high density lipoprotein. Significance: This is the first study to demonstrate that self-association of apolipoprotein A-I attunes key steps in reverse cholesterol transport.

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Disruption of the C-terminal helix by single amino acid deletion is directly responsible for impaired cholesterol efflux ability of apolipoprotein A-I Nichinan

Cited by 21 publications

References 57 publications

Structure of Apolipoprotein A-I N Terminus on Nascent High Density Lipoproteins

Structure of Apolipoprotein A-I N Terminus on Nascent High Density Lipoproteins

Naturally occurring variant of mouse apolipoprotein A-I alters the lipid and HDL association properties of the protein

Impact of Self-association on Function of Apolipoprotein A-I

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