10.1126/science.1135308
https://zenodo.org/records/1230874
oai:zenodo.org:1230874
Kimchi-Sarfaty, C.
C.
Kimchi-Sarfaty
Oh, J. M.
J. M.
Oh
0000-0002-1836-1707
Kim, I.-W.
I.-W.
Kim
Sauna, Z. E.
Z. E.
Sauna
Calcagno, A. M.
A. M.
Calcagno
Ambudkar, S. V.
S. V.
Ambudkar
Gottesman, M. M.
M. M.
Gottesman
A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity
Zenodo
2007
2007-01-26
Creative Commons Zero v1.0 Universal
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.