ABCA4 - Explore the Science & Experts | ideXlab

Scan Science and Technology

Contact Leading Edge Experts & Companies

ABCA4

The Experts below are selected from a list of 14346 Experts worldwide ranked by ideXlab platform

Robert S Molday – One of the best experts on this subject based on the ideXlab platform.

  • Localization and functional characterization of the p.Asn965Ser (N965S) ABCA4 variant in mice reveal pathogenic mechanisms underlying Stargardt macular degeneration.
    Human Molecular Genetics, 2017
    Co-Authors: Laurie L Molday, Daniel J. Wahl, Marinko V. Sarunic, Robert S Molday

    Abstract:

    ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) proteins that transports N-retinylidene-phosphatidylethanolamine (N-Ret-PE) across outer segment disc membranes thereby facilitating the removal of potentially toxic retinoid compounds from photoreceptor cells. Mutations in the gene encoding ABCA4 are responsible for Stargardt disease (STGD1), an autosomal recessive retinal degenerative disease that causes severe vision loss. To define the molecular basis for STGD1 associated with the p.Asn965Ser (N965S) mutation in the Walker A motif of nucleotide binding domain 1 (NBD1), we generated a p.Asn965Ser knockin mouse and compared the subcellular localization and molecular properties of the disease variant with wild-type (WT) ABCA4. Here, we show that the p.Asn965Ser ABCA4 variant expresses at half the level of WT ABCA4, partially mislocalizes to the endoplasmic reticulum (ER) of photoreceptors, is devoid of N-Ret-PE activated ATPase activity, and causes an increase in autofluorescence and the bisretinoid A2E associated with lipofuscin deposits in retinal pigment epithelial cells as found in Stargardt patients and ABCA4 knockout mice. We also show for the first time that a significant fraction of WT ABCA4 is retained in the inner segment of photoreceptors. On the basis of these studies we conclude that loss in substrate-dependent ATPase activity and protein misfolding are mechanisms underlying STGD1 associated with the p.Asn965Ser mutation in ABCA4. Functional and molecular modeling studies further suggest that similar pathogenic mechanisms are responsible for Tangiers disease associated with the p.Asn935Ser (N935S) mutation in the NBD1 Walker A motif of ABCA1.

  • differential phospholipid substrates and directional transport by atp binding cassette proteins abca1 abca7 and ABCA4 and disease causing mutants
    Journal of Biological Chemistry, 2013
    Co-Authors: Faraz Quazi, Robert S Molday

    Abstract:

    Abstract ABCA1, ABCA7, and ABCA4 are members of the ABCA subfamily of ATP-binding cassette transporters which share extensive sequence and structural similarity. Mutations in ABCA1 cause Tangier disease characterized by defective cholesterol homeostasis and high-density lipoprotein (HDL) deficiency. Mutations in ABCA4 are responsible for Stargardt disease, a degenerative disorder associated with severe loss in central vision. Although cell-based studies have implicated ABCA proteins in lipid transport, the substrates and direction of transport have not been firmly established. We have purified and reconstituted ABCA1, ABCA7 and ABCA4 into liposomes for fluorescent-lipid transport studies. ABCA1 actively exported or flipped phosphatidylcholine (PC), phosphatidylserine (PS), and sphingomyelin (SM) from the cytoplasmic to the exocytoplasmic leaflet of membranes, whereas ABCA7 preferentially exported PS. In contrast ABCA4 transported phosphatidylethanolamine (PE) in the reverse direction. The same phospholipids stimulated the ATPase activity of these ABCA transporters. The transport activity and ATPase activity of ABCA1 and ABCA4 was reduced by 25% in the presence of 20% cholesterol. Nine ABCA1 Tangier mutants and corresponding ABCA4 Stargardt mutants showed significantly reduced phospholipid transport activity and subcellular mislocalization. These studies provide the first direct evidence for ABCA1 and ABCA7 functioning as phospholipid transporters and suggest that this activity is an essential step in the loading of ApoA-1 with phospholipids for HDL formation.

  • differential phospholipid substrates and directional transport by atp binding cassette proteins abca1 abca7 and ABCA4 and disease causing mutants
    Journal of Biological Chemistry, 2013
    Co-Authors: Faraz Quazi, Robert S Molday

    Abstract:

    ABCA1, ABCA7, and ABCA4 are members of the ABCA subfamily of ATP-binding cassette transporters that share extensive sequence and structural similarity. Mutations in ABCA1 cause Tangier disease characterized by defective cholesterol homeostasis and high density lipoprotein (HDL) deficiency. Mutations in ABCA4 are responsible for Stargardt disease, a degenerative disorder associated with severe loss in central vision. Although cell-based studies have implicated ABCA proteins in lipid transport, the substrates and direction of transport have not been firmly established. We have purified and reconstituted ABCA1, ABCA7, and ABCA4 into liposomes for fluorescent-lipid transport studies. ABCA1 actively exported or flipped phosphatidylcholine, phosphatidylserine, and sphingomyelin from the cytoplasmic to the exocytoplasmic leaflet of membranes, whereas ABCA7 preferentially exported phosphatidylserine. In contrast, ABCA4 transported phosphatidylethanolamine in the reverse direction. The same phospholipids stimulated the ATPase activity of these ABCA transporters. The transport and ATPase activities of ABCA1 and ABCA4 were reduced by 25% in the presence of 20% cholesterol. Nine ABCA1 Tangier mutants and the corresponding ABCA4 Stargardt mutants showed significantly reduced phospholipid transport activity and subcellular mislocalization. These studies provide the first direct evidence for ABCA1 and ABCA7 functioning as phospholipid transporters and suggest that this activity is an essential step in the loading of apoA-1 with phospholipids for HDL formation.

Silvia C Finnemann – One of the best experts on this subject based on the ideXlab platform.

  • expression of ABCA4 in the retinal pigment epithelium and its implications for stargardt macular degeneration
    Proceedings of the National Academy of Sciences of the United States of America, 2018
    Co-Authors: Tamara L Lenis, Jane Hu, Sze Yin Ng, Zhichun Jiang, Shanta Sarfare, Marcia Lloyd, Nicholas J Esposito, William Samuel, Cynthia Jaworski, Silvia C Finnemann

    Abstract:

    Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the ABCA4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in ABCA4−/− mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. (i) By in situ hybridization analysis and by RNA-sequencing analysis, we show the ABCA4 mRNA is expressed in human and mouse RPE cells. (ii) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. (iii) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk−/− but not ABCA4−/− mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the ABCA4−/− background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic ABCA4−/− mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1.

  • expression of ABCA4 in the retinal pigment epithelium and its implications for stargardt macular degeneration
    Proceedings of the National Academy of Sciences of the United States of America, 2018
    Co-Authors: Tamara L Lenis, Jane Hu, Sze Yin Ng, Zhichun Jiang, Shanta Sarfare, Marcia Lloyd, Nicholas J Esposito, William Samuel, Cynthia Jaworski, Silvia C Finnemann

    Abstract:

    Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the ABCA4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in ABCA4−/− mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. (i) By in situ hybridization analysis and by RNA-sequencing analysis, we show the ABCA4 mRNA is expressed in human and mouse RPE cells. (ii) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. (iii) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk−/− but not ABCA4−/− mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the ABCA4−/− background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic ABCA4−/− mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1.

Faraz Quazi – One of the best experts on this subject based on the ideXlab platform.

  • differential phospholipid substrates and directional transport by atp binding cassette proteins abca1 abca7 and ABCA4 and disease causing mutants
    Journal of Biological Chemistry, 2013
    Co-Authors: Faraz Quazi, Robert S Molday

    Abstract:

    Abstract ABCA1, ABCA7, and ABCA4 are members of the ABCA subfamily of ATP-binding cassette transporters which share extensive sequence and structural similarity. Mutations in ABCA1 cause Tangier disease characterized by defective cholesterol homeostasis and high-density lipoprotein (HDL) deficiency. Mutations in ABCA4 are responsible for Stargardt disease, a degenerative disorder associated with severe loss in central vision. Although cell-based studies have implicated ABCA proteins in lipid transport, the substrates and direction of transport have not been firmly established. We have purified and reconstituted ABCA1, ABCA7 and ABCA4 into liposomes for fluorescent-lipid transport studies. ABCA1 actively exported or flipped phosphatidylcholine (PC), phosphatidylserine (PS), and sphingomyelin (SM) from the cytoplasmic to the exocytoplasmic leaflet of membranes, whereas ABCA7 preferentially exported PS. In contrast ABCA4 transported phosphatidylethanolamine (PE) in the reverse direction. The same phospholipids stimulated the ATPase activity of these ABCA transporters. The transport activity and ATPase activity of ABCA1 and ABCA4 was reduced by 25% in the presence of 20% cholesterol. Nine ABCA1 Tangier mutants and corresponding ABCA4 Stargardt mutants showed significantly reduced phospholipid transport activity and subcellular mislocalization. These studies provide the first direct evidence for ABCA1 and ABCA7 functioning as phospholipid transporters and suggest that this activity is an essential step in the loading of ApoA-1 with phospholipids for HDL formation.

  • differential phospholipid substrates and directional transport by atp binding cassette proteins abca1 abca7 and ABCA4 and disease causing mutants
    Journal of Biological Chemistry, 2013
    Co-Authors: Faraz Quazi, Robert S Molday

    Abstract:

    ABCA1, ABCA7, and ABCA4 are members of the ABCA subfamily of ATP-binding cassette transporters that share extensive sequence and structural similarity. Mutations in ABCA1 cause Tangier disease characterized by defective cholesterol homeostasis and high density lipoprotein (HDL) deficiency. Mutations in ABCA4 are responsible for Stargardt disease, a degenerative disorder associated with severe loss in central vision. Although cell-based studies have implicated ABCA proteins in lipid transport, the substrates and direction of transport have not been firmly established. We have purified and reconstituted ABCA1, ABCA7, and ABCA4 into liposomes for fluorescent-lipid transport studies. ABCA1 actively exported or flipped phosphatidylcholine, phosphatidylserine, and sphingomyelin from the cytoplasmic to the exocytoplasmic leaflet of membranes, whereas ABCA7 preferentially exported phosphatidylserine. In contrast, ABCA4 transported phosphatidylethanolamine in the reverse direction. The same phospholipids stimulated the ATPase activity of these ABCA transporters. The transport and ATPase activities of ABCA1 and ABCA4 were reduced by 25% in the presence of 20% cholesterol. Nine ABCA1 Tangier mutants and the corresponding ABCA4 Stargardt mutants showed significantly reduced phospholipid transport activity and subcellular mislocalization. These studies provide the first direct evidence for ABCA1 and ABCA7 functioning as phospholipid transporters and suggest that this activity is an essential step in the loading of apoA-1 with phospholipids for HDL formation.

  • Posttranslational Modifications of the Photoreceptor-Specific ABC Transporter ABCA4
    Biochemistry, 2011
    Co-Authors: Yaroslav Tsybovsky, Faraz Quazi, Robert S Molday, Benlian Wang, Krzysztof Palczewski

    Abstract:

    ABCA4 is a photoreceptor-specific ATP-binding cassette transporter implicated in the clearance of all-trans-retinal produced in the retina during light perception. Multiple mutations in this protein have been linked to Stargardt disease and other visual disorders. Here we report the first systematic study of posttranslational modifications in native ABCA4 purified from bovine rod outer segments. Seven N-glycosylation sites were detected in exocytoplasmic domains 1 and 2 by mass spectrometry, confirming the topological model of ABCA4 proposed previously. The modifying oligosaccharides were relatively short and homogeneous, predominantly representing a high-mannose type of N-glycosylation. Five phosphorylation sites were detected in cytoplasmic domain 1, with four of them located in the linker “regulatory-like” region conserved among ABCA subfamily members. Contrary to published results, phosphorylation of ABCA4 was found to be independent of light. Using human ABCA4 mutants heterologously expressed in mamm…