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#intrinsicallydisorderedregions

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Amelia Cervera 🧬

mRNA 3′UTRs chaperone intrinsically disordered regions to control protein activity.

#RNA #mRNA #3UTR #IntrinsicallyDisorderedRegions #IDRs #IntrinsicallyDisorderedProteins #Chaperones #Preprint

biorxiv.org/content/10.1101/20

bioRxiv · mRNA 3′UTRs chaperone intrinsically disordered regions to control protein activityMore than 2,700 human mRNA 3′UTRs have hundreds of highly conserved (HC) nucleotides, but their biological roles are unclear. Here, we show that mRNAs with HC 3′UTRs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. These proteins are only fully active when translated from mRNA templates that include their 3′UTRs, raising the possibility of functional interactions between 3′UTRs and IDRs. Rather than affecting protein abundance or localization, we find that HC 3′UTRs control transcriptional or histone demethylase activity through co-translationally determined protein oligomerization states that are kinetically stable. 3′UTR-dependent changes in protein folding require mRNA-IDR interactions, suggesting that mRNAs act as IDR chaperones. These mRNAs are multivalent, a biophysical RNA feature that enables their translation in network-like condensates, which provide favorable folding environments for proteins with long IDRs. These data indicate that the coding sequence is insufficient for the biogenesis of biologically active conformations of IDR-containing proteins and that RNA can catalyze protein folding. ### Competing Interest Statement The authors have declared no competing interest. Pershing Square Foundation, https://ror.org/04tce9s05 G. Harold & Leila Y. Mathers Foundation National Institutes of Health, DP1GM123454, R35GM144046 Memorial Sloan Kettering Cancer Center, https://ror.org/02yrq0923, P30 CA008748
Amelia Cervera 🧬

Longer Internal Exons Tend to Have More Tandem Repeats and Experience Insertions and Deletions More Frequently

#Indels #IntrinsicallyDisorderedRegions #IDRs #TandemRepeats #Preprint

biorxiv.org/content/10.1101/20

bioRxiv · Longer Internal Exons Tend to Have More Tandem Repeats and Experience Insertions and Deletions More FrequentlyInsertions and deletions (indels) within the coding sequences of eukaryotic proteins are known to preferentially encode intrinsically disordered regions (IDRs), protein regions that by themselves do not form unique three-dimensional structures. As a previous investigation of our group showed that long internal exons have a tendency to encode IDRs in eukaryotes (Fukuchi et al. 2023), it was thought worthwhile to analyse how indels alter internal exons and affect IDRs of the encoded proteins. For consideration of evolutionary roles indels play, it is important to focus on indels commonly observed in all variants ('fixed' indels) since indels in minor variants may represent transient aberrations in splicing. Here, by comparison of orthologous variants of closely related species together with those of outgroups, fixed indels in the internal exons were identified in four mammals and two flies. Deletion tends to occur more frequently than insertion does and indels are generally more prevalent in long internal exons. On average 51% of inserted and 40% of deleted residues are attributable to alterations in tandem repeats. Nearly all indel lengths are multiples of three nucleotides (nt), shorter than 19 nt and mostly encode IDRs. Intriguingly, it was discovered that tandem repeats preferentially occur in long internal exons. As tandem repeats mostly encode IDRs, this finding at least partially explains the high incidence of IDRs in long internal exons. We propose that long internal exons had been produced in early eukaryotes mainly by repeat expansion but are experiencing frequent indels by alterations in tandem repeats. ### Competing Interest Statement The authors have declared no competing interest.
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