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Updated: Jun 10, 2026
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Defining Hsp33's Redox-regulated Chaperone Activity and Mapping Conformational Changes on Hsp33 Using Hydrogen-deuterium Exchange Mass Spectrometry
Published on: June 7, 2018
mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity
Yang Luo1, Yaofeng Zhong2, Sudipto Basu1
1Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, NY 10065, USA.
Cell
|June 8, 2026
Summary
Highly conserved mRNA 3' untranslated regions (UTRs) act as chaperones for intrinsically disordered regions (IDRs). These mRNA 3' UTRs prevent co-translational misfolding, ensuring the proper function of transcriptional regulators.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Over 2,700 human mRNA 3' UTRs contain highly conserved nucleotides with unknown biological functions.
- These mRNAs encode proteins rich in intrinsically disordered regions (IDRs) featuring hydrophobic amino acid clusters.
- The role of mRNA 3' UTRs in regulating protein activity, particularly for proteins with IDRs, remains largely unexplored.
Purpose of the Study:
- To investigate the biological roles of highly conserved nucleotides in human mRNA 3' UTRs.
- To determine how mRNA 3' UTRs influence the activity of proteins encoded by these transcripts, focusing on those with IDRs.
- To elucidate the mechanism by which mRNA 3' UTRs regulate protein folding and function.
Main Methods:
- Analysis of conserved nucleotides in human mRNA 3' UTRs.
- Investigating the co-translational folding of JMJD3 protein using the KDM6B 3' UTR.
- Assessing the impact of 3' UTRs on protein activity, abundance, and localization.
- Examining the structural properties of 3' UTRs, including their multivalent and condensate-enriched nature.
Main Results:
- Human mRNA 3' UTRs with conserved nucleotides control the activity of specific proteins like MYC, UTX, and JMJD3.
- The KDM6B 3' UTR co-translationally modulates JMJD3 protein folding by promoting IDR-IDR interactions and preventing domain misfolding.
- This suggests a novel RNA-mediated chaperone activity for IDRs, crucial for preventing interference with structured domain folding.
- 3' UTRs exhibiting chaperone activity are multivalent and enriched in condensates, forming localized folding environments.
Conclusions:
- mRNA 3' UTRs play a critical role in regulating the activity of IDR-containing transcriptional regulators.
- Protein sequence alone is insufficient for the biogenesis of fully active IDR-containing proteins in cells.
- mRNA 3' UTRs act as crucial regulators, preventing co-translational misfolding and ensuring proper protein function.
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