A "silent" polymorphism in the MDR1 gene changes substrate specificity.
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.
Kimchi-Sarfaty
Chava
C
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. kimchi@cber.fda.gov
Oh
Jung Mi
JM
Kim
In-Wha
IW
Sauna
Zuben E
ZE
Calcagno
Anna Maria
AM
Ambudkar
Suresh V
SV
Gottesman
Michael M
MM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D003062:Codon; D016572:Cyclosporine / Q000494:pharmacology; D019450:Genes, MDR; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000378:metabolism / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013379:Substrate Specificity; D014162:Transfection; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003062:Codon; D012333:RNA, Messenger; D020112:Rhodamine 123; D016572:Cyclosporine; D014700:Verapamil; D020123:Sirolimus