New & Noteworthy

Something from Nothing: A New, Structured Protein from Noncoding DNA

November 01, 2017


In the Rick and Morty episode Mortynight Run, a gaseous life form pulls off what alchemists had been trying to do for centuries. It literally creates gold out of thin air!

GaseousGold

Like this gaseous being converting oxygen into gold, Saccharomyces cerevisiae has converted noncoding DNA into a protein with at least some secondary structure. (Reddit)

Our ever faithful friend, Saccharomyces cerevisiae can’t do that (at least not yet). But what it has done is create a protein, Bsc4p, out of noncoding intergenic DNA. And while not gold, it is a fully functioning protein.

In a new study, Bungard and coworkers show that this recently evolved gene, BSC4, encodes a protein that can fold into at least a partially defined structure. This matters as there was some debate about whether newly generated proteins could attain a defined structure or if they would remain as intrinsically disordered proteins (IDPs). A reasonable debate, given how rare structure is among amino acid sequences and how plentiful IDPs are in a cell.

Bsc4p is a great protein to study in this regard as there is very strong evidence that it has evolved relatively recently in S. cerevisiae, but not in other closely related species. And it definitely does work in a S. cerevisiae cell. While not essential, some genetic studies (including this one) indicate that it plays an important role in DNA damage repair pathways.

Here is an example from S. paradoxus of the noncoding sequence that the S .cerevisiae BSC4 gene almost certainly sprang from:

gtg TCT GTA ATT CTA CGG AAA AGT AAA CAA AAA AAC TGT AAT TGC ATA ACG AGC AAT TTA TAT ACA ATA CAC ATA GAA AGA CTT TCG CTC tga TGT CCG AAC TGC CAT TGT CAT TGG AGA AAA TCC TTA TGT GGA GTG GAG TTC CCT GCA GGT TAT TTT CAG AGA AAA CGT GGT TAC AAA AAG GGA CCA GAT TCG CCC tag CTT ACA ACT CGC TTG AAT CAT CTT TAT GCC AGA CCT TTC AAC GCC GCG ACC CCA AAA ACA taa ATG CTG AGT CAC CAT GGT GCT GGG CGC TGT CGC TGT CGC GCT GTT CCT TTC CGA GAA AAG CAC GGC AAC AAC AAC AAC AGT CCA TAT GAC CAA AAA AAA AAT AAC CGC AAA TGG CAG tga AAT GCA ATT ATC ATT GTA TAC GA?

In order for this sequence to become a gene coding a protein, at a minimum the first lowercase, dark orange codon needs to be mutated to ATG, a start codon, and the rest of the lowercase, dark orange codons need to be mutated away from being stop codons.

This seems to be part of what happened in S. cerevisiae:

ATG TCT ATT GTG CTA CGG AAG AGT AAC AAA AAA AAC AAA AAC TGC ATA ACA AGC AAG TTT TAT ACA ATA CAC ATT ATA AAA ATT TCT ACT CCG GTG TTC CGA GCT CCC ATT GCC ATT GGA GAA AGC CCT TAT GTG GAG TGG AGC TGC CTA CAG GTT GTT TTC AGG AAA GAC ATG GTT ACA AAA AAG ACG ACA TTC GCC CAA CTT ATC ACT CGC TTG AAC CAC TTT TTA TGC CAA GCC CTT AAA CGC CGC GAC TCA AAA ACA TAC ATA CTG TGC CGC ACG GCA GTT TTT GGC GCT ATG ACA CCC TTT TCC CCA AGA AAA TCG CAT ATT AAC AAC AAA TTA CCC ATG CAA CCC AGG AAA AAA AAA ATA GTC ATT ATA TAC GTA GTG CGC TTT CAT TGA

Through a few small changes, we now have a 131 amino acid polypeptide where before we had some noncoding DNA between LYP1 and ALP1.

Bungard and coworkers use a variety of techniques to show that this newly evolved protein has structure. Not as much structure as many proteins that have been around longer, but more than many of those IDPs.

PhilStone

It is as if Saccharomyces cerevisiae has found the philosopher’s stone but instead of changing lead to gold, it turns noncoding DNA into a gene that codes for a partially structured protein. (Wikimedia Commons)

Consistent with protein structure, Bsc4p forms compact oligomers under native conditions that are partially resistant to proteolysis, has a far UV circular dichroism (CD) spectra consistent with beta sheets, has a buried tryptophan, Trp47, that becomes solvent accessible under denaturing conditions, as measured by tryptophan fluorescence, and has a near UV spectra consistent with a hydrophobic core. However, they found no evidence of any significant interactions between the secondary structures to form a single three dimensional shape, in the protein.  In other words, no evidence of a tertiary structure.

And that wasn’t the only sign that Bsc4p wasn’t a mature, fully structured protein. For example, that near UV CD that showed a hydrophobic core, was weak in intensity, which is consistent with at least “partially molten character.” And Bsc4p bound certain dyes: Congo red, Thioflavin T, and ANS, in a way consistent with some molten globule and/or amyloid character.

So we have a bit of a mixed bag with Bsc4p. One way to think about it is as a young protein still developing its ultimate three dimensional structure. Or, it could be that for the job it does, this is all the structure it needs.

In any event, it is definitely a newly evolved protein with at least some structure which shows that this can indeed happen. Sometimes Mother Nature can make structured proteins from noncoding DNA. Like that gaseous being on Rick and Morty, producing gold out of thin air.

by Barry Starr, Ph.D., Director of Outreach Activities, Stanford Department of Genetics

Categories: Research Spotlight

Tags: noncoding DNA , protein structure , BSC4 , newly evolved gene

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