The multidrug resistance P-glycoprotein. Oligomeric state and intramolecular interactions

The human multidrug resistance P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) superfamily of transporters, is frequently responsible for the failure of chemotherapy by virtue of its ability to export hydrophobic cytotoxic drugs from cells. Elucidating the inter- and intramolecular...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-09, Vol.276 (39), p.36075-36078
Main Authors: Taylor, J C, Horvath, A R, Higgins, C F, Begley, G S
Format: Article
Language:English
Subjects:
ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry
ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism
Cell Line
Detergents - pharmacology
DNA - metabolism
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Epitopes - chemistry
Humans
Octoxynol - pharmacology
Precipitin Tests
Protein Binding
Protein Biosynthesis
Protein Structure, Tertiary
TAP1 protein
TAP2 protein
Two-Hybrid System Techniques
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Summary:The human multidrug resistance P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) superfamily of transporters, is frequently responsible for the failure of chemotherapy by virtue of its ability to export hydrophobic cytotoxic drugs from cells. Elucidating the inter- and intramolecular interactions of this protein is critical to understanding its cellular function and mechanism of action. Toward this end, we have used both biochemical and genetic techniques to probe potential oligomerization interactions of P-gp. Differentially epitope-tagged P-gp molecules did not co-immunoprecipitate when co-expressed in HEK293 cells or when co-translated in vitro, demonstrating that P-gp is monomeric in both the presence and absence of detergents. The two cytoplasmic domains of P-gp did not interact with each other in vivo when co-expressed as gene fusions in yeast. In contrast, the homologous domains of the transporter associated with antigen processing (TAP), which reside on separate polypeptides and must form a heterodimeric transporter (TAP1/TAP2), did interact in this system, suggesting a role for these domains in TAP dimerization. Implications for understanding the subunit organization of ABC transporters are discussed.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C100345200