Silent SNPs serve up a structural surprise

The biology textbooks need a rewrite, at least when it comes to the long-standing dogma that it’s the sequence of amino acids that dictates the structure and function of a protein.   

In a surprising paper, published in Science, researchers in the US and South Korea have identified different versions of the same protein built from an identical string of amino acids but with different biochemical properties.   

This unexpected finding  comes about because of a single nucleotide polymorphism (SNP), says Michael Gottesman of the National Cancer Institute in Bethesda, Maryland. This doesn’t alter the amino acid sequence of the gene product - a mammalian membrane pump called P-glycoprotein (P-gp) - but does change its ability to pump certain molecules, he said.   

Gottesman’s hunch is that the apparently ’silent’ SNP has an effect on the rate of translation from mRNA to protein, thereby disrupting the assembly of the P-gp pump. It’s a bit like coiling up a garden hose, he suggests. If a gardener proceeds slowly and steadily, the hose coils up nice and neatly. If, however, the task is rushed, the hose ends up in a horrible mess. 

’Proteins this big fold and insert in the membrane while they are being translated,’ said Gottesman. ’Even small changes in the rate of translation can change protein folding in a subtle way that affects the ability of the protein to interact with substrates and inhibitors.’

The idea that protein structure and function can be affected by changes in the translation rate without changes in the amino acid sequence is intriguing. ’Regardless of the mechanism, this paper will undoubtedly stimulate new work in this area that could fundamentally change our understanding of how proteins fold in cells,’ says Bill Skach, professor of biochemistry and molecular biology at Oregon Health Sciences University. ’It is difficult to know how widespread this phenomenon might be at this point, but there have been hints that silent mutations in a number of diseases may affect protein function,’ he said.

Gottesman agreed. A cancer patient with this ’silent’ mutation in the gene encoding P-gp would have cells with an altered sensitivity to certain drugs, which could help to explain why some fail to respond to treatment.

And other proteins could be similarly affected, he speculated. The skin disorder pseudoxanthoma elasticum, for example, is caused by mutations in a gene encoding another transporter protein. Yet the amino acid sequence of the protein is normal in around 40 per cent of patients.’Our guess is that there will be other examples of this, especially among multitransmembrane proteins.’ 

Henry Nicholls