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A "silent" polymorphism in the MDR1 gene changes substrate specificity.
Science. 2007 Jan 26; 315(5811): 525-8.
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.
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Login or register to post commentsAnother mechanism by which synonymous mutations may affect protein function is by altering the kinetics of protein folding. Researchers have proposed that synonymous substitutions that change a codon read by an abundant tRNA to a codon read by a rare tRNA could
http://feeds.nature.com/~r/chemistry/rss/the_sceptical_chymist_with_comm...
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...when it specifies a different fold! At least that's the latest word from Kimchi-Sarfaty et. al., who reported in the Jan 26 issue of Science that a supposedly "silent" mutation in the multidrug resistance gene MDR1 changes the function of the encoded protein.
http://www.gnxp.com/blog/2007/02/when-is-synonymous-sequence-not.php
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MDR: Multi Drug Resistance Protein. It's an ABC (ATPase Box Cassette) Transporter. In other words, this gene encodes an energy utilizing pump that sits on the plasma membrane and actively transports (mostly hydrophobic?) compounds out of the cell. As I wrote
http://www.scienceblogs.com/transcript/2007/02/silent_nucleotide_change_...
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A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity Science 26 January 2007 Vol. 315. no. 5811, pp. 525 - 528Chava Kimchi-Sarfaty, Jung Mi Oh, In-Wha Kim, Zuben E. Sauna, Anna Maria Calcagno, Suresh V. Ambudkar, Michael M. Gottesman Abstract:
http://yannklimentidis.blogspot.com/2007/01/synonymous-snps-not-so-silen...
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Pim van Meurs has a blog post at The Panda's Thumb about the recent paper on translational selection on a synonymous polymorphic site in a eukaryotic gene (DOI link). He points out that this was predicted in a paper from 1987. In short, the rate of translation
http://www.scienceblogs.com/evolgen/2007/01/silent_mutations_continue_to...
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In 1988, Purvis et al proposed an interesting hypothesis about silent mutations:Purvis IJ, Bettany AJ, Santiago TC, Coggins JR, Duncan K, Eason R, Brown AJ. The efficiency of folding of some proteins is increased by controlled rates of translation in vivo.
http://www.pandasthumb.org/archives/2007/01/an_evolutionary_1.html
