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3 results on '"Drazul D"'

1. Analysis of Chimeric Receptors Shows That Multiple Distinct Functional Activities of Scavenger Receptor, Class B, Type I (SR-BI), Are Localized to the Extracellular Receptor Domain

Author

Margery A. Connelly, George H. Rothblat, Seth M. Klein, Drazul D, Stoudt G, de la Llera-Moya M, Pascale Monzo, Fournier N, David L. Williams, and P. G. Yancey

Subjects
CD36 Antigens, Cytoplasm, Cholesterol oxidase, Recombinant Fusion Proteins, CD36, Biological Transport, Active, Biochemistry, Cell membrane, Mice, chemistry.chemical_compound, medicine, Extracellular, Animals, Humans, Receptors, Immunologic, Scavenger receptor, Receptor, Receptors, Lipoprotein, Receptors, Scavenger, biology, Cholesterol, Cell Membrane, Membrane Proteins, Scavenger Receptors, Class B, Peptide Fragments, Protein Structure, Tertiary, Rats, Cell biology, medicine.anatomical_structure, chemistry, COS Cells, biology.protein, Cholesteryl ester, lipids (amino acids, peptides, and proteins), Cholesterol Esters, Extracellular Space, Lipoproteins, HDL
Abstract

Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without degradation of the HDL particle. In addition, SR-BI stimulates the bi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC from plasma HDL. SR-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanced sensitivity of membrane cholesterol to extracellular cholesterol oxidase. In contrast, CD36, a closely related class B scavenger receptor, has none of these activities despite binding HDL with high affinity. In the present study, analyses of chimeric SR-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activities related to HDL CE selective uptake, bi-directional FC flux, and the alteration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI. The N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma membrane. The C-terminal tail of SR-BI is dispensable for activity as well for targeting to the plasma membrane. Thus, multiple distinct functional activities are localized to the SR-BI extracellular domain.

Published
2001

2. Scavenger receptor class B type I affects cholesterol homeostasis by magnifying cholesterol flux between cells and HDL.

Author

de La Llera-Moya, M, Connelly, M A, Drazul, D, Klein, S M, Favari, E, Yancey, P G, Williams, D L, and Rothblat, G H

Abstract

Results from several laboratories clearly indicate that expression of scavenger receptor class B type I (SR-BI) enhances the bidirectional flux of cholesterol between cells and lipoproteins. Because the activity of HMG-CoA reductase, the key enzyme in cholesterol biosynthesis, is regulated by cell cholesterol content, we designed experiments to investigate the effect of SR-BI expression on the activity of this enzyme and on net cellular cholesterol mass. In addition, we compared the function of SR-BI with its human homolog, CD36 and LIMPII analogous 1. Our experiments demonstrate that both receptors enhance the flux of unesterified or free cholesterol bidirectionally, down a concentration gradient. Receptor-mediated cholesterol flux can effectively modulate multiple aspects of cellular cholesterol metabolism, including the pool that regulates the activity of HMG-CoA reductase. We also found that constitutive expression of SR-BI alters the steady state level of cellular cholesterol and phospholipid when SR-BI-expressing cells are maintained in medium containing serum lipoproteins. All of these effects are proportional to the level of receptor on the cell surface. These data indicate that the level of SR-BI expression determines both the rate of free cholesterol flux and the steady state level of cellular cholesterol.

Published
2001

3. Analysis of chimeric receptors shows that multiple distinct functional activities of scavenger receptor, class B, type I (SR-BI), are localized to the extracellular receptor domain.

Author

Connelly MA, de la Llera-Moya M, Monzo P, Yancey PG, Drazul D, Stoudt G, Fournier N, Klein SM, Rothblat GH, and Williams DL

Subjects
Animals, Biological Transport, Active genetics, CD36 Antigens chemistry, CD36 Antigens genetics, CD36 Antigens metabolism, COS Cells, Cell Membrane chemistry, Cell Membrane genetics, Cell Membrane metabolism, Cell Membrane physiology, Cholesterol metabolism, Cholesterol Esters metabolism, Cytoplasm chemistry, Cytoplasm genetics, Cytoplasm metabolism, Extracellular Space genetics, Extracellular Space physiology, Humans, Lipoproteins, HDL metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Protein Structure, Tertiary genetics, Rats, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Receptors, Scavenger, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Scavenger Receptors, Class B, Extracellular Space metabolism, Membrane Proteins physiology, Receptors, Immunologic physiology, Receptors, Lipoprotein, Recombinant Fusion Proteins physiology
Abstract

Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without degradation of the HDL particle. In addition, SR-BI stimulates the bi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC from plasma HDL. SR-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanced sensitivity of membrane cholesterol to extracellular cholesterol oxidase. In contrast, CD36, a closely related class B scavenger receptor, has none of these activities despite binding HDL with high affinity. In the present study, analyses of chimeric SR-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activities related to HDL CE selective uptake, bi-directional FC flux, and the alteration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI. The N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma membrane. The C-terminal tail of SR-BI is dispensable for activity as well for targeting to the plasma membrane. Thus, multiple distinct functional activities are localized to the SR-BI extracellular domain.

Published
2001
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