Journal article Open Access

A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity

Kimchi-Sarfaty, C.; Oh, J. M.; Kim, I.-W.; Sauna, Z. E.; Calcagno, A. M.; Ambudkar, S. V.; Gottesman, M. M.

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. A rare, but synonymous, codon in alleles of a drug-resistance gene can change translation kinetics and so produce a conformationally distinct protein species. A rare, but synonymous, codon in alleles of a drug-resistance gene can change translation kinetics and so produce a conformationally distinct protein species.

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