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mRNA 3'UTRs chaperone intrinsically disordered regions to control protein activity
Yang Luo1, Yaofeng Zhong1,2, Sudipto Basu1
1Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, NY 10065, USA.
Biorxiv : the Preprint Server for Biology
|July 9, 2025
Summary
Highly conserved mRNA 3'UTRs (untranslated regions) encode proteins with intrinsically disordered regions (IDRs). These 3'UTRs are crucial for protein folding and function, acting as chaperones.
Area of Science:
- Molecular Biology
- Biophysics
- Genetics
Background:
- Hundreds of highly conserved nucleotides exist in over 2,700 human mRNA 3'UTRs.
- The biological functions of these conserved regions remain largely unknown.
Purpose of the Study:
- To investigate the biological roles of highly conserved (HC) mRNA 3'UTRs.
- To explore the relationship between HC 3'UTRs and the proteins they encode, particularly those with intrinsically disordered regions (IDRs).
Main Methods:
- Analysis of mRNA 3'UTRs and encoded protein sequences.
- Investigation of protein activity, folding, and oligomerization states.
- Biophysical characterization of mRNA features and translation in condensates.
Main Results:
- mRNAs with HC 3'UTRs predominantly encode proteins with long intrinsically disordered regions (IDRs).
- HC 3'UTRs are essential for the full activity of these proteins, influencing transcriptional or histone demethylase activity.
- mRNA-IDR interactions facilitate 3'UTR-dependent protein folding, suggesting mRNAs act as chaperones for IDR-containing proteins.
- Multivalent mRNAs enable translation in condensates, creating favorable folding environments.
Conclusions:
- The coding sequence alone is insufficient for the proper folding of IDR-containing proteins.
- RNA, specifically HC 3'UTRs, can catalyze protein folding, acting as a chaperone mechanism.
- This highlights a novel role for mRNA structure in determining protein biogenesis and function.
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