Publication Date:
2006-12-23
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimchi-Sarfaty, Chava -- Oh, Jung Mi -- Kim, In-Wha -- Sauna, Zuben E -- Calcagno, Anna Maria -- Ambudkar, Suresh V -- Gottesman, Michael M -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2007 Jan 26;315(5811):525-8. Epub 2006 Dec 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. kimchi@cber.fda.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17185560" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
Cell Membrane/metabolism
;
Cercopithecus aethiops
;
Codon
;
Cyclosporine/pharmacology
;
*Genes, MDR
;
Haplotypes
;
HeLa Cells
;
Humans
;
Mutagenesis, Site-Directed
;
P-Glycoprotein/antagonists & inhibitors/*chemistry/genetics/*metabolism
;
*Polymorphism, Single Nucleotide
;
Protein Biosynthesis
;
Protein Conformation
;
*Protein Folding
;
Protein Structure, Tertiary
;
RNA, Messenger/genetics/metabolism
;
Reverse Transcriptase Polymerase Chain Reaction
;
Rhodamine 123/metabolism/pharmacology
;
Sirolimus/pharmacology
;
Substrate Specificity
;
Transfection
;
Verapamil/metabolism/pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink