Sodium taurocholate-dependent lipid efflux by ABCA1: effects of W590S mutation on lipid translocation and apolipoprotein A-I dissociation

Nagao, Kazunori; Zhao, Yu; Takahashi, Kei; Kimura, Yasuhisa; Ueda, Kazumitsu

doi:10.1194/jlr.m800597-jlr200

Cited by 46 publications

(59 citation statements)

References 37 publications

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“…ATP were examined. When Alexa 546-labeled apoA-I was added to the medium, apoA-I bound to ABCA1-expressing HEK293 cells within 10 min but not to the parental HEK293 cells, as previously reported ( 24,28 ) ( Fig. 2A ).…”

Section: Atp Bindingsupporting

confidence: 84%

ATP hydrolysis-dependent conformational changes in the extracellular domain of ABCA1 are associated with apoA-I binding

Nagao

Takahashi²,

Azuma³

et al. 2012

Journal of Lipid Research

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Section: Atp Bindingsupporting

confidence: 84%

ATP hydrolysis-dependent conformational changes in the extracellular domain of ABCA1 are associated with apoA-I binding

Nagao

Takahashi²,

Azuma³

et al. 2012

Journal of Lipid Research

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“…2D). This timescale of 10 min is comparable to that of apoA-I binding to cells expressing ABCA1 (16). These results suggest that apoA-I, upon binding to ABCA1, induces dissociation of ABCA1 dimers into fast-diffusing monomers.…”

Section: Abca1 Is Immobilized On the Plasma Membrane Depending On Itsmentioning

confidence: 60%

“…Digits in parentheses represent the number of cells examined. from ABCA1 within 1 min after binding (16); apoA-I undergoes a conformational transition in response to lipids (17); and lipidated apoA-I can no longer interact with ABCA1 (5, 18).…”

Section: Abca1 Is Immobilized On the Plasma Membrane Depending On Itsmentioning

confidence: 99%

ABCA1 dimer–monomer interconversion during HDL generation revealed by single-molecule imaging

Nagata

Nakada

Kasai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The generation of high-density lipoprotein (HDL), one of the most critical events for preventing atherosclerosis, is mediated by ATPbinding cassette protein A1 (ABCA1). ABCA1 is known to transfer cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I) for generating discoidal HDL (dHDL) particles, composed of 100-200 lipid molecules surrounded by two apoA-I molecules; however, the regulatory mechanisms are still poorly understood. Here we observed ABCA1-GFP and apoA-I at the level of single molecules on the plasma membrane via a total internal reflection fluorescence microscope. We found that about 70% of total ABCA1-GFP spots are immobilized on the plasma membrane and estimated that about 89% of immobile ABCA1 molecules are in dimers. Furthermore, an ATPase-deficient ABCA1 mutant failed to be immobilized or form a dimer. We found that the lipid acceptor apoA-I interacts with the ABCA1 dimer to generate dHDL and is followed by ABCA1 dimermonomer interconversion. This indicates that the formation of the ABCA1 dimer is the key for apoA-I binding and nascent HDL generation. Our findings suggest the physiological significance of conversion of the ABCA1 monomer to a dimer: The dimer serves as a receptor for two apoA-I molecules for dHDL particle generation.membrane protein | transporter P lasma high-density lipoprotein (HDL) is critical for preventing coronary artery disease (1). A member of the ATPdependent transporter family of ABC proteins, ATP-binding cassette protein A1 (ABCA1) initiates the generation of discoidal HDL (dHDL), a bilayer fragment consisting of 100-200 lipids wrapped by two molecules of apolipoprotein A-I (apoA-I) (2-4), by exporting cholesterol and phospholipids to lipid-free apoA-I in serum (5). More than 70 mutations have been identified in the ABCA1 gene. Indeed, mutations in ABCA1 lead to Tangier disease, which is characterized by plasma HDL deficiency (6-10). ABCA1 has two large extracellular domains (ECDs), and the two intramolecular disulfide bonds between them are necessary for apoA-I binding and HDL formation (11-13) (Fig. 1A). Two pieces of evidence suggest that apoA-I interacts with a specific conformation of the ECDs in an ATP-dependent manner: Chemical cross-linkers can cross-link apoA-I with ABCA1, and ATPasedeficient ABCA1 mutants fail to mediate apoA-I binding and crosslinking. However, the importance of direct binding of ABCA1-apoA-I in HDL formation is still controversial and, furthermore, how a dHDL particle containing two molecules of apoA-I is formed from lipid-free apoA-I monomers and membrane lipids is unknown.To address these issues, we performed single-molecule fluorescence imaging (14, 15) of ABCA1 and apoA-I on the plasma membrane (PM) via a total internal reflection fluorescence (TIRF) microscope in living cells. We examined the dynamic behaviors of ABCA1 as well as the interaction of ABCA1 with apoA-I, and found that ABCA1 forms an immobile dimer on the PM; the ABCA1 dimer then dissociates into diffusing monomers upon interaction with apoA-I, finally gen...

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“…HEK293 cells stably expressing human ABCA1 fused with GFP at the C terminus were established as described ( 23 ). …”

Section: Cell Culturementioning

confidence: 99%

“…1C, D ). Whereas plasma apoA-I functions as a lipid acceptor for ABCA1 in vivo, NaTC can function as a lipid acceptor for ABCA1 in vitro ( 23 ). Therefore, we investigated whether enhanced lipid effl ux through ABCA1 after SM depletion would also be observed in the presence of NaTC.…”

Section: Sm Depletion Exerts Opposite Effects On the Lipid-export Actmentioning

confidence: 99%

ABCB4 exports phosphatidylcholine in a sphingomyelin-dependent manner

Zhao

Ishigami

Nagao

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org bile ( 1 ). Phospholipid secretion into bile is important for the protection of the canalicular membrane against the strong detergent action of bile salts, which aid in absorption of cholesterol from food. Dysfunction of ABCB4 results in a lack of phospholipids and surplus of bile salts in primary bile, and this compositional imbalance causes damage to biliary canaliculi followed by chronic and progressive liver disease, such as intrahepatic cholestasis and lowphospholipid-associated cholelithiasis syndrome ( 2-5 ). ABCB4 shares quite high (86%) amino-acid sequence similarity ( 6 ) with multidrug resistance protein 1 (ABCB1), an ATP-dependent multidrug exporter ( 7 ). We have demonstrated that ABCB4 also functions as an ATP-dependent exporter by showing that PC and cholesterol are exported from cultured cells expressing the wild-type human ABCB4, but not from cells expressing an ATP-hydrolysis-defi cient mutant of ABCB4, when bile salts are present in the medium ( 8 ).ABCA1 exports excess cellular cholesterol and PC to the extracellular lipid acceptor apoA-I to generate HDL and plays a major role in cholesterol homeostasis and HDL metabolism. ABCG1, another member of the ABC proteins, is also involved in these processes. ABCG1 exports cholesterol and SM when HDL, but not apoA-I, is added to the medium as the lipid acceptor ( 9 ). We have shown that the decrease in cellular SM content in the plasma membrane reduces cholesterol export by ABCG1, and that the function of ABCG1 is dependent on SM ( 10, 11 ). By contrast, reduced Abstract ABCB4, which is specifi cally expressed on the canalicular membrane of hepatocytes, exports phosphatidylcholine (PC) into bile. Because SM depletion increases cellular PC content and stimulates PC and cholesterol effl ux by ABCA1, a key transporter involved in generation of HDL, we predicted that SM depletion also stimulates PC effl ux through ABCB4. To test this prediction, we compared the lipid effl ux activity of ABCB4 and ABCA1 under SM depletion induced by two different types of inhibitors for SM synthesis, myriocin and ( 1R,3S )-N -(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, in human embryonic kidney 293 and baby hamster kidney cells. Unexpectedly, SM depletion exerted opposite effects on ABCB4 and ABCA1, suppressing PC effl ux through ABCB4 while stimulating effl ux through ABCA1. Both ABCB4 and ABCA1 were recovered from Triton-X-100-soluble membranes, but ABCB4 was mainly recovered from CHAPS-insoluble SM-rich membranes, whereas ABCA1 was recovered from CHAPS-soluble membranes. These results suggest that a SM-rich membrane environment is required for ABCB4 to function. ABCB4 must have evolved to exert its maximum activity in the SM-rich membrane environment of the canalicular membrane, where it transports PC as the physiological substrate. Press, January 19, 2015 DOI 10.1194 ABCB4 exports phosphatidylcholine in a sphingomyelindependent manner Abbreviations: BHK, baby hamster kidney; CERT, ceramide transfer ...

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Sodium taurocholate-dependent lipid efflux by ABCA1: effects of W590S mutation on lipid translocation and apolipoprotein A-I dissociation

Cited by 46 publications

References 37 publications

ATP hydrolysis-dependent conformational changes in the extracellular domain of ABCA1 are associated with apoA-I binding

ATP hydrolysis-dependent conformational changes in the extracellular domain of ABCA1 are associated with apoA-I binding

ABCA1 dimer–monomer interconversion during HDL generation revealed by single-molecule imaging

ABCB4 exports phosphatidylcholine in a sphingomyelin-dependent manner

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