mRNA 3′UTRs chaperone intrinsically disordered regions to control protein activity.
#RNA #mRNA #3UTR #IntrinsicallyDisorderedRegions #IDRs #IntrinsicallyDisorderedProteins #Chaperones #Preprint
More 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
Serious diseases—ranging from emphysema and cystic fibrosis to Alzheimer's disease—can result when the 🔹cellular oversight of protein folding goes awry🔹.
Identifying the glyco-code responsible for high-fidelity folding and quality control could be a promising way for drug therapies to target many diseases.
Scientists once thought that the single code governing life was #DNA, and that everything was governed by how DNA's four building blocks—A, C, G and T—combined and recombined.
But in recent decades, it has become clear that there are other codes at work, and especially in building the intricately folded, secreted proteins that are created in 🔸the human cell's protein factory, the "endoplasmic reticulum" (ER)🔸, a membrane-enclosed compartment where protein folding begins.
Approximately 7,000 different proteins—one-third of all the proteins in the human body—mature in the ER.
The secreted proteins—collectively known as the "#secretome"—are responsible for everything from our body's enzymes to its immune and digestive systems and must be formed correctly for the human body to function normally.
Special molecules called "#chaperones," help fold the protein into its final shape.
They also help to identify proteins that haven't folded quite correctly, lending them additional help in refolding, or, if they're hopelessly misfolded, targeting them for destruction before they cause damage.
However, the chaperone system itself, which comprises a part of the cell's quality control department, sometimes fails, and when it does, the results can be catastrophic for our health.
The discovery of the carbohydrate-based chaperone system in the ER was due to the pioneering work that 👉Daniel Hebert, professor of biochemistry and molecular biology at UMass Amherst and one of the paper's senior authors, initiated as a postdoctoral fellow in the 1990s.
"The tools we have now, including glycoproteomics and mass spectrometry at UMass Amherst's Institute for Applied Life Sciences, are allowing us to answer questions that have remained open for over 25 years," says Hebert. "The lead author of this new paper, 👉Kevin Guay, is doing things I could only dream of when I first started."
Among the most pressing of these unanswered questions is: ♦️how do chaperones know when 7,000 different origami-like proteins are correctly folded?♦️
We know now that the answer involves an "ER gatekeeper" enzyme known as #UGGT, and a host of carbohydrate tags, called "N-glycans", which are linked to specific sites in the protein's amino acid sequence.
Guay, who is completing his Ph.D. in the molecular cellular biology program at UMass Amherst, focused on two specific mammalian proteins, known as "alpha-1 antitrypsin" and "antithrombin".
⭐️Using CRISPR-edited cells, he and his co-authors modified the ER chaperone network to determine how the presence and location of N-glycans affected protein folding.
They watched as the disease variants were recognized by the ER gatekeeper UGGT and, in order to peer more closely, developed a number of innovative glycoproteomics techniques using mass spectrometry to understand what happens to the glycans that stud the surface of the proteins.
What they discovered is that ⚠️the enzyme UGGT "tags" misfolded proteins with sugars placed in specific positions. ⚠️
It's a sort of code that the chaperones can then read to determine exactly where the folding process went wrong and how to fix it.
"This is the first time that we've been able to see where UGGT puts sugars on proteins made in human cells for quality control," says Guay.
"We now have a platform for extending our understanding of how sugar tags can send proteins for further quality control steps and our work suggests that UGGT is a promising avenue for targeted drug therapy research."
"What's so exciting about this research," says👉 Lila Gierasch, distinguished professor of biochemistry and molecular biology at UMass Amherst and one of the paper's co-authors, "is the discovery that glycans act as a code for protein folding in the ER.
The discovery of the role that UGGT plays opens the door to future advancement in understanding and eventually treating the hundreds of diseases that result from misfolded proteins."
https://phys.org/news/2023-12-cellular-code-protein-therapeutic-avenues.html
Postdoctoral Research Fellow in Proteostasis and Aging
UNC Charlotte
Postdoctoral research position available to study gut-to-muscle stress signaling and its role in aging #chaperones #Proteostasis #C. elegans
See the full job description on jobRxiv: https://jobrxiv.org/job/unc-charlotte-27778-postdoctoral-research-fellow-in-proteostasis-and-aging/?feed_id=54832
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https://jobrxiv.org/job/unc-charlotte-27778-postdoctoral-research-fellow-in-proteostasis-and-aging/?feed_id=54832
11-May-2023
How “extracellular chaperones” help remove abnormal proteins
Researchers discover how wrongly folded proteins occurring outside cells are degraded, thereby preventing them from causing health problems.
https://www.eurekalert.org/news-releases/988935
When exposed to stressful conditions, several proteins tend to misfold and form aggre-gates inside or outside cells. These aggregates, if accumulated, may contribute to age-related disorders, including Alzheimer’s disease. Extracellular chaperones stabilize mis-folded proteins to prevent their aggregation and have been implicated in clearing these defective proteins outside cells, but their mechanisms are poorly understood. Now, re-searchers from Chiba University have developed an assay that can detect this process quantitatively and have uncovered that extracellular chaperones mediate the lysosomal degradation of extracellular misfolded proteins.
Open position: research technician & lab manager in #biochemistry/#protein-production.
Get involved in research projects in #structuralbiology in an international setting @ISTAustria
& take responsibility in our lab.
Work on #chaperones, #enzymes & more.
Open Positions The Institute of Science and Technology Austria (ISTA) offers career opportunities at many different stages, both in science and in scientific support and administration. The Institute is committed to supporting all employees in achieving their goals, and in further developing the
Study reveals #genetic mechanism of divergent thermo-tolerance in penaeid #shrimp.
#aquaculture #climatechange #ACD #chaperones
https://phys.org/news/2023-04-reveals-genetic-mechanism-divergent-thermo-tolerance.html
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