ABCG5 - Explore the Science & Experts | ideXlab



Scan Science and Technology

Contact Leading Edge Experts & Companies

ABCG5

The Experts below are selected from a list of 15945 Experts worldwide ranked by ideXlab platform

ABCG5 – Free Register to Access Experts & Abstracts

Helen H Hobbs – One of the best experts on this subject based on the ideXlab platform.

  • structural role of ABCG5 abcg8 in sterol transport
    Biophysical Journal, 2017
    Co-Authors: Jyh-yeuan Lee, Daniel M. Rosenbaum, Helen H Hobbs

    Abstract:

    ATP binding cassette (ABC) transporters play critical roles in maintaining sterol homeostasis in eukaryotic organisms, including yeast, plants and mammals. In humans, the heterodimeric ABCG5/ABCG8 (G5G8) mediates the excretion of cholesterol and dietary plant sterols into bile and into the gut lumen. Mutations inactivating either ABCG5 or ABCG8 cause sitosterolemia, a rare autosomal recessive genetic disorder characterized by plant sterol accumulation, hypercholesterolemia, and premature coronary atherosclerosis. ABCG5 and ABCG8 are half ABC transporters;each subunit consists of an N-terminal nucleotide-binding domain (NBD) and a C-terminal transmembrane domain (TMD). The NBDs dimerize to form two catalytically asymmetric nucleotide-binding sites (NBS), one that is catalytically active (NBS2) and the other inactive (NBS1). To understand the structural basis for G5G8-mediated sterol transport we developed a large-scale purification of human G5G8 by exploiting Pichia patoris yeast. We crystallized the transporter in lipid bilayers, solved its structure in a nucleotide-free state at 3.9 A resolution, and generated the first atomic model of an ABC sterol transporter. G5G8 presents a new structural configuration for the TMD of ABC transporters, which is present in a large and functionally diverse ABC2 superfamily. We discover that the TMD and the NBS are coupled through networks of interactions that differ between NBS1 and NBS2, reflecting the catalytic asymmetry of the transporter. A series of conserved polar residues in the TMD form polar networks that we proposed play a role in transmitting signals from the ATPase catalysis in the NBS to sterol transport on the TMD. Molecular dynamic simulation and long-range coevolution analysis revealed an inward-upward TMD movement that predicts a significant conformational change between the TMD subunits. Thus, the G5G8 structure provides a molecular framework that allows us to propose a mechanistic model for ABC transporter-mediated sterol transport and to analyze the disruptive effects of mutations causing sitosterolemia. The structure will serve as a structural template for homology modelling to a wide range of transport system that is regulated by ABCG transporters and by ABC2 superfamily.

    Free Register to Access Article

  • Structural Role of ABCG5/ABCG8 in Sterol Transport
    Biophysical Journal, 2017
    Co-Authors: Jyh-yeuan Lee, Daniel M. Rosenbaum, Helen H Hobbs

    Abstract:

    ATP binding cassette (ABC) transporters play critical roles in maintaining sterol homeostasis in eukaryotic organisms, including yeast, plants and mammals. In humans, the heterodimeric ABCG5/ABCG8 (G5G8) mediates the excretion of cholesterol and dietary plant sterols into bile and into the gut lumen. Mutations inactivating either ABCG5 or ABCG8 cause sitosterolemia, a rare autosomal recessive genetic disorder characterized by plant sterol accumulation, hypercholesterolemia, and premature coronary atherosclerosis. ABCG5 and ABCG8 are half ABC transporters;each subunit consists of an N-terminal nucleotide-binding domain (NBD) and a C-terminal transmembrane domain (TMD). The NBDs dimerize to form two catalytically asymmetric nucleotide-binding sites (NBS), one that is catalytically active (NBS2) and the other inactive (NBS1). To understand the structural basis for G5G8-mediated sterol transport we developed a large-scale purification of human G5G8 by exploiting Pichia patoris yeast. We crystallized the transporter in lipid bilayers, solved its structure in a nucleotide-free state at 3.9 A resolution, and generated the first atomic model of an ABC sterol transporter. G5G8 presents a new structural configuration for the TMD of ABC transporters, which is present in a large and functionally diverse ABC2 superfamily. We discover that the TMD and the NBS are coupled through networks of interactions that differ between NBS1 and NBS2, reflecting the catalytic asymmetry of the transporter. A series of conserved polar residues in the TMD form polar networks that we proposed play a role in transmitting signals from the ATPase catalysis in the NBS to sterol transport on the TMD. Molecular dynamic simulation and long-range coevolution analysis revealed an inward-upward TMD movement that predicts a significant conformational change between the TMD subunits. Thus, the G5G8 structure provides a molecular framework that allows us to propose a mechanistic model for ABC transporter-mediated sterol transport and to analyze the disruptive effects of mutations causing sitosterolemia. The structure will serve as a structural template for homology modelling to a wide range of transport system that is regulated by ABCG transporters and by ABC2 superfamily.

    Free Register to Access Article

  • selective sterol accumulation in ABCG5 abcg8 deficient mice
    Journal of Lipid Research, 2004
    Co-Authors: Klaus Von Bergmann, Helen H Hobbs, Dieter Lutjohann, Jonathan Cohen

    Abstract:

    The ATP binding cassette (ABC) transporters ABCG5 and ABCG8 limit intestinal absorption and promote biliary secretion of neutral sterols. Mutations in either gene cause sitosterolemia, a rare recessive disease in which plasma and tissue levels of several neutral sterols are in- creased to varying degrees. To determine why patients with sitosterolemia preferentially accumulate noncholesterol ste- rols, levels of cholesterol and the major plant sterols were compared in plasma, liver, bile, and brain of wild-type and ABCG5/ABCG8-deficient ( G5G8 � / � ) mice. The total sterol content of liver and plasma was similar in G5G8 � / � mice and wild-type animals despite an � 30-fold increase in non- cholesterol sterol levels in the knockout animals. The relative enrichment of each sterol in the plasma and liver of G5G8 � / � mice (stigmasterolsitosterolcholestanolbassicas- terolcampesterolcholesterol) reflected its relative en- richment in the bile of wild-type mice. These results indi- cate that 24-alkylated, � 22 , and 5 � -reduced sterols are preferentially secreted into bile and that preferential biliary secretion of noncholesterol sterols by ABCG5 and ABCG8 prevents the accumulation of these sterols in normal ani- mals. The mRNA levels for 13 enzymes in the cholesterol biosynthetic pathway were reduced in the livers of the G5G8 � / � mice, despite a 50% reduction in hepatic choles- terol level. Thus, the accumulation of sterols other than cholesterol is sensed by the cholesterol regulatory machin- ery. —Yu, L., K. von Bergmann, D. Lutjohann, H. H. Hobbs, and J. C. Cohen. Selective sterol accumulation in ABCG5/ ABCG8-deficient mice. J. Lipid Res. 2004. 45: 301-307.

    Free Register to Access Article

Albert K. Groen – One of the best experts on this subject based on the ideXlab platform.

  • hepatic ABCG5 g8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage to feces rct
    Atherosclerosis, 2015
    Co-Authors: Arne Dikkers, Jan Freark De Boer, Albert K. Groen, Uwe J. F. Tietge

    Abstract:

    Abstract Background and aims Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT. Methods Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic ABCG5/g8 overexpression in wild-types. Results In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p  Conclusions ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic ABCG5/g8 expression for enhancing RCT are not likely to be successful.

    Free Register to Access Article

  • Hepatic ABCG5/G8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage-to-feces RCT.
    Atherosclerosis, 2015
    Co-Authors: Arne Dikkers, Jan Freark De Boer, Albert K. Groen, Uwe J. F. Tietge

    Abstract:

    Abstract Background and aims Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT. Methods Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic ABCG5/g8 overexpression in wild-types. Results In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p  Conclusions ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic ABCG5/g8 expression for enhancing RCT are not likely to be successful.

    Free Register to Access Article

  • the sterol transporting heterodimer ABCG5 abcg8 requires bile salts to mediate cholesterol efflux
    FEBS Letters, 2007
    Co-Authors: Carlos L J Vrins, Edwin Vink, Kristin E. Vandenberghe, Raoul J. J. M. Frijters, Jurgen Seppen, Albert K. Groen

    Abstract:

    The ATP binding cassette transporters ABCG5 and ABCG8 are indispensable for hepatobiliary cholesterol transport. In this study, we investigated the specificity of the heterodimer for cholesterol acceptors. Dog gallbladder epithelial cells were mono- or double-transfected with lentiviral mouse ABCG5 and Abcg8 vectors. Double-transfected cells showed increased efflux to different bile salt (BS) species, while mono-transfected cells did not show enhanced efflux. The efflux was initiated at micellar concentrations and addition of phosphatidylcholine increased efflux. Cholesterol secretion was highly BS dependent, whereas other cholesterol acceptors such as ApoAI, HDL or methyl-β-cyclodextrin did not elicit ABCG5/g8 dependent cholesterol secretion.

    Free Register to Access Article

Jyh-yeuan Lee – One of the best experts on this subject based on the ideXlab platform.

  • Picky ABCG5/G8 and promiscuous ABCG2 – a tale of fatty diets and drug toxicity.
    FEBS letters, 2020
    Co-Authors: Narakorn Khunweeraphong, James Mitchell‐white, Dániel Szöllősi, Toka O.k. Hussein, Karl Kuchler, Ian D. Kerr, Thomas Stockner, Jyh-yeuan Lee

    Abstract:

    Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily-G ATP-binding cassette (ABCG) transporters and disclose putative substrate binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bundles, the membrane-embedded polar relay, the re-entry helices, and a hydrophobic valve. Interestingly, ABCG2 shows extreme substrate promiscuity, whereas ABCG5/G8 transport only sterol molecules. ABCG2 structures suggest a large internal cavity, serving as a binding region for substrates and inhibitors, while mutational and pharmacological analyses support the notion of multiple binding sites. By contrast, ABCG5/G8 shows a collapsed cavity of insufficient size to hold substrates. Indeed, mutational analyses indicate a sterol-binding site at the hydrophobic interface between the transporter and the lipid bilayer. In this review, we highlight key differences and similarities between ABCG2 and ABCG5/G8 structures. We further discuss the relevance of distinct and shared structural features in the context of their physiological functions. Finally, we elaborate on how ABCG2 and ABCG5/G8 could pave the way for studies on other ABCG transporters.

    Free Register to Access Article

  • picky ABCG5 g8 and promiscuous abcg2 a tale of fatty diets and drug toxicity
    FEBS Letters, 2020
    Co-Authors: Narakorn Khunweeraphong, Dániel Szöllősi, Toka O.k. Hussein, Karl Kuchler, Ian D. Kerr, Thomas Stockner, James Mitchellwhite, Jyh-yeuan Lee

    Abstract:

    Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily-G ATP-binding cassette (ABCG) transporters and disclose putative substrate binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bundles, the membrane-embedded polar relay, the re-entry helices, and a hydrophobic valve. Interestingly, ABCG2 shows extreme substrate promiscuity, whereas ABCG5/G8 transport only sterol molecules. ABCG2 structures suggest a large internal cavity, serving as a binding region for substrates and inhibitors, while mutational and pharmacological analyses support the notion of multiple binding sites. By contrast, ABCG5/G8 shows a collapsed cavity of insufficient size to hold substrates. Indeed, mutational analyses indicate a sterol-binding site at the hydrophobic interface between the transporter and the lipid bilayer. In this review, we highlight key differences and similarities between ABCG2 and ABCG5/G8 structures. We further discuss the relevance of distinct and shared structural features in the context of their physiological functions. Finally, we elaborate on how ABCG2 and ABCG5/G8 could pave the way for studies on other ABCG transporters.

    Free Register to Access Article

  • ABCG5 g8 a structural view to pathophysiology of the hepatobiliary cholesterol secretion
    Biochemical Society Transactions, 2019
    Co-Authors: Aiman A. Zein, Gregory A Graf, Toka O.k. Hussein, Rupinder Kaur, Jyh-yeuan Lee

    Abstract:

    The ABCG5/G8 heterodimer is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion. Inactivating mutations on either the ABCG5 or ABCG8 subunit cause Sitosterolemia, a rare genetic disorder. In 2016, a crystal structure of human ABCG5/G8 in an apo state showed the first structural information on ATP-binding cassette (ABC) sterol transporters and revealed several structural features that were observed for the first time. Over the past decade, several missense variants of ABCG5/G8 have been associated with non-Sitosterolemia lipid phenotypes. In this review, we summarize recent pathophysiological and structural findings of ABCG5/G8, interpret the structure-function relationship in disease-causing variants and describe the available evidence that allows us to build a mechanistic view of ABCG5/G8-mediated sterol transport.

    Free Register to Access Article