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

@article{citeulike:1048863, 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. 10.1126/science.1135308}, address = {Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Present address: Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Room 316, Bethesda, MD 20892, USA.}, author = {Kimchi-Sarfaty, Chava and Oh, Jung M. and Kim, In-Wha and Sauna, Zuben E. and Calcagno, Anna M. and Ambudkar, Suresh V. and Gottesman, Michael M.}, citeulike-article-id = {1048863}, citeulike-linkout-0 = {http://dx.doi.org/10.1126/science.1135308}, citeulike-linkout-1 = {http://www.sciencemag.org/cgi/content/abstract/315/5811/525}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17185560}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17185560}, day = {26}, doi = {10.1126/science.1135308}, issn = {1095-9203}, journal = {Science}, keywords = {abcb1, mdr1, polymorphism, synonymous}, month = {January}, number = {5811}, pages = {525--528}, posted-at = {2009-07-22 15:09:35}, priority = {2}, title = {A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity}, url = {http://dx.doi.org/10.1126/science.1135308}, volume = {315}, year = {2007} }

TY - JOUR ID - citeulike:1048863 L3 - citeulike-article-id:1048863 N2 - 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. 10.1126/science.1135308 IS - 5811 JF - Science SN - 1095-9203 AD - Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Present address: Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Room 316, Bethesda, MD 20892, USA. EP - 528 TI - A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity VL - 315 SP - 525 KW - abcb1 KW - mdr1 KW - polymorphism KW - synonymous AU - Kimchi-Sarfaty, Chava AU - Oh, Jung AU - Kim, In-Wha AU - Sauna, Zuben AU - Calcagno, Anna AU - Ambudkar, Suresh AU - Gottesman, Michael PY - 2007/01/26/ UR - http://dx.doi.org/10.1126/science.1135308 ER -