A "Silent" Polymorphism in the MDR 1 Gene Changes Substrate Specificity
Open accessAbstract
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 ( MDR 1) gene, part of a haplotype previously linked to altered function of the MDR 1 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.
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Some proteins require delayed translation for appropriate folding, which is guaranteed by uncommon codons.
“For appropriate folding, some proteins require delayed translation, which is guaranteed by uncommon codons (Kimchi-Sarfaty et al. 2007).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Kimchi-Sarfaty et al. 2007
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- Authors
- Kimchi-Sarfaty, C., Oh, J. M., Kim, I.-W., Sauna, Z. E., Calcagno, A. M., Ambudkar, S. V., & Gottesman, M. M.
- Affiliations
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
- National Cancer Institute (US)
- Corresponding author
- Oh, Jung Mi
- Gottesman, Michael M.
- Venue
- Science
- Published
- 2007-01-26
- Volume
- 315
- Issue
- 5811
- Pages
- 525-528
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2058864686
- Cited by
- 2,416
- References
- 1
- Citations by year
- 2026: 37 · 2025: 48 · 2024: 81 · 2023: 68 · 2022: 89 · 2021: 108 · 2020: 86 · 2019: 94 · 2018: 101 · 2017: 111 · 2016: 117 · 2015: 129 · 2014: 157 · 2013: 181 · 2012: 170
- FWCI
- 81.22
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- public-domain
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Keywords
- MDR1 gene, P-glycoprotein, synonymous single nucleotide polymorphism, silent polymorphism, substrate specificity, drug transport inhibition, co-translational folding, membrane protein insertion, protein conformation, haplotypes
- MeSH terms
- Animals, Cell Line, Cell Membrane, Chlorocebus aethiops, Codon, Haplotypes, HeLa Cells, Humans, Protein Conformation, RNA, Messenger, Substrate Specificity, Transfection, Protein Biosynthesis, Verapamil, Mutagenesis, Site-Directed, Cyclosporine, Protein Structure, Tertiary, Protein Folding, Genes, MDR, Rhodamine 123, Sirolimus, Reverse Transcriptase Polymerase Chain Reaction, ATP Binding Cassette Transporter, Subfamily B, Member 1, Polymorphism, Single Nucleotide
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