ATP-binding Cassette Transporter A1 Contains a Novel C-terminal VFVNFA Motif That Is Required for Its Cholesterol Efflux and ApoA-I Binding Activities

Fitzgerald, Michael L.; Okuhira, Keiichiro; Short, Glenn; Manning, Jennifer J.; Bell, Susan A.; Freeman, Mason W.

doi:10.1074/jbc.m409848200

Cited by 66 publications

(67 citation statements)

References 43 publications

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“…The C-terminal VFVNFA motif of ABCA1 has been shown to be essential for its lipid efflux activity. Alteration of this motif did not prevent trafficking of the transporter to the plasma membrane, but did eliminate apoA-I binding to ABCA1 (108). Interestingly, one substitution mutation (W590S), however, reduces apolipoprotein-mediated lipid efflux severely but increased apoA-I binding moderately (105).…”

Section: Resultsmentioning

confidence: 94%

The Interaction of ApoA-I and ABCA1 Triggers Signal Transduction Pathways to Mediate Efflux of Cellular Lipids

Zhao

Yin

et al. 2011

Mol Med

100

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Reverse cholesterol transport (RCT) has been characterized as a crucial step for antiatherosclerosis, which is initiated by ATPbinding cassette A1 (ABCA1) to mediate the efflux of cellular phospholipids and cholesterol to lipid-free apolipoprotein A-I (apoA-I). However, the mechanisms underlying apoA-I/ABCA1 interaction to lead to the lipidation of apoA-I are poorly understood. There are several models proposed for the interaction of apoA-I with ABCA1 as well as the lipidation of apoA-I mediated by ABCA1. ApoA-I increases the levels of ABCA1 protein markedly. In turn, ABCA1 can stabilize apoA-I. The interaction of apoA-I with ABCA1 could activate signaling molecules that modulate posttranslational ABCA1 activity or lipid transport activity. The key signaling molecules in these processes include protein kinase A (PKA), protein kinase C (PKC), Janus kinase 2 (JAK2), Rho GTPases and Ca 2+ , and many factors also could influence the interaction of apoA-I with ABCA1. This review will summarize these mechanisms for the apoA-I interaction with ABCA1 as well as the signal transduction pathways involved in these processes.

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Section: Resultsmentioning

confidence: 94%

The Interaction of ApoA-I and ABCA1 Triggers Signal Transduction Pathways to Mediate Efflux of Cellular Lipids

Zhao

Yin

et al. 2011

Mol Med

100

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“…Therefore, we assessed the mRNA levels of the cholesterol efflux transporter ATP-binding cassette 1 (ABCA1), which regulates the rate-controlling step in the removal of cellular cholesterol by transferring cholesterol and phospholipids to an apolipoprotein acceptor (Fitzgerald et al 2004). Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol (Bodzioch et al 1999).…”

Section: Resultsmentioning

confidence: 99%

Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function

Clement

Gamerdinger

Tamboli

et al. 2009

Journal of Neurochemistry

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Chronic oxidative stress has been causally linked to several neurodegenerative disorders. As sensitivity for oxidative stress greatly differs between brain regions and neuronal cell types, specific cellular mechanisms of adaptation to chronic oxidative stress should exist. Our objective was to identify molecular mechanisms of adaptation of neuronal cells after applying chronic sublethal oxidative stress. We demonstrate that cells resistant to oxidative stress exhibit altered cholesterol and sphingomyelin metabolisms. Stress‐resistant cells showed reduced levels of molecules involved in cholesterol trafficking and intracellular accumulation of cholesterol, cholesterol precursors, and metabolites. Moreover, stress‐resistant cells exhibited reduced SMase activity. The altered lipid metabolism was associated with enhanced autophagy. Treatment of stress‐resistant cells with neutral SMase reversed the stress‐resistant phenotype, whereas it could be mimicked by treatment of neuronal cells with a specific inhibitor of neutral SMase. Analysis of hippocampal and cerebellar tissue of mouse brains revealed that the obtained cell culture data reflect the in vivo situation. Stress‐resistant cells in vitro showed similar features as the less vulnerable cerebellum in mice, whereas stress‐sensitive cells resembled the highly sensitive hippocampal area. These findings suggest an important role of the cell type‐specific lipid profile for differential vulnerabilities of different brain areas toward chronic oxidative stress.

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“…These results suggest that segments of ABCA4 downstream of the VFVNFA motif enhance the basal ATPase activity of ABCA4 and ABCA1, whereas segments of ABCA1 downstream of this motif reduce the basal ATPase activity of these transporters. The basal activities, however, do not appear to reflect the true function of these transporters, since the ABCA1-⌬46 mutant has been reported to be defective in cholesterol efflux (28).…”

Section: Differential Effect Of C-terminal Deletion and Chimera Mutatmentioning

confidence: 99%

Role of the C Terminus of the Photoreceptor ABCA4 Transporter in Protein Folding, Function, and Retinal Degenerative Diseases

Ming¹,

Molday

2009

Journal of Biological Chemistry

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ABCA4 is an ATP-binding cassette transporter that is expressed in rod and cone photoreceptor cells and implicated in the removal of retinal derivatives from outer segments following photoexcitation. Mutations in the ABCA4 gene are responsible for a number of related retinal degenerative diseases, including Stargardt macular degeneration, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. In order to determine the role of the C terminus of ABCA4 in protein structure and function and understand mechanisms by which C-terminal mutations cause retinal degenerative diseases, we have expressed and purified a series of deletion and substitution mutants of ABCA4 and ABCA1 in HEK 293T cells for analysis of their cellular localization and biochemical properties. Removal of the C-terminal 30 amino acids of ABCA4, including a conserved VFVNFA motif, resulted in a loss in N-retinylidene-phosphatidylethanolamine substrate binding, ATP photoaffinity labeling, and retinal-stimulated ATPase activity. This mutant was also retained in the endoplasmic reticulum of cells. Replacement of the VFVNFA motif with alanine residues also resulted in loss in function and cellular mislocalization. In contrast, C-terminal deletion mutants that retain the VFVNFA motif were functionally active and localized to intracellular vesicles similar to wild-type ABCA4. Our studies indicated that the VFVNFA motif is required for the proper folding of ABCA4 into a functionally active protein. This motif also contributes to the efficient folding of ABCA1 into an active protein. Our results provide a molecular based rationale for the disease phenotype displayed by individuals with mutations in the C terminus of ABCA4.ABCA4, also known as ABCR or the rim protein, is a member of the ABCA subfamily of ATP binding cassette transporters expressed in vertebrate photoreceptor cells (1-4). It is localized along the rims and incisures of rod and cone outer segment discs, where it has been implicated in the binding and transport of the Schiff base adduct of all-trans-retinal and phosphatidylethanolamine (PE) 3 known as N-retinylidene-PE or N-ret-PE across disc membranes as part of visual cycle (3, 5-9).To date, over 500 different mutations in the ABCA4 gene are known to cause Stargardt macular degeneration, an early onset recessive disease characterized by the loss in central vision, the presence of lipofuscin deposits in retinal pigment epithelial cells, a delay in dark adaptation, and progressive degeneration of photoreceptor and retinal pigment epithelial cells (1, 10 -15). Mutations in ABCA4 are also responsible for other related but more severe retinal degenerative diseases, including autosomal recessive cone-rod dystrophy and retinitis pigmentosa (16 -19). Finally, individuals heterozygous for selected diseaselinked mutations in ABCA4 have been suggested to be at higher risk in developing age-related macular degeneration (20). Disease-associated mutations are distributed throughout the ABCA4 gene and comprise missense, splice site, an...

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ATP-binding Cassette Transporter A1 Contains a Novel C-terminal VFVNFA Motif That Is Required for Its Cholesterol Efflux and ApoA-I Binding Activities

Cited by 66 publications

References 43 publications

The Interaction of ApoA-I and ABCA1 Triggers Signal Transduction Pathways to Mediate Efflux of Cellular Lipids

The Interaction of ApoA-I and ABCA1 Triggers Signal Transduction Pathways to Mediate Efflux of Cellular Lipids

Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function

Role of the C Terminus of the Photoreceptor ABCA4 Transporter in Protein Folding, Function, and Retinal Degenerative Diseases

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