Abstract
Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Animals
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Cell Line
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Cell Membrane / metabolism
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Chlorocebus aethiops
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Codon
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Cyclosporine / pharmacology
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Genes, MDR*
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Haplotypes
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HeLa Cells
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Humans
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Mutagenesis, Site-Directed
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Polymorphism, Single Nucleotide*
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Protein Biosynthesis
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Protein Conformation
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Protein Folding*
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Protein Structure, Tertiary
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Rhodamine 123 / metabolism
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Rhodamine 123 / pharmacology
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Sirolimus / pharmacology
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Substrate Specificity
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Transfection
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Verapamil / metabolism
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Verapamil / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Codon
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RNA, Messenger
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Rhodamine 123
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Cyclosporine
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Verapamil
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Sirolimus