Cell's Quality Control May Miss Half of Certain Misfolded Proteins

A new study led by scientists at Penn State has found that proteins with a certain kind of "entanglement" in their normal structure are more likely to misfold — and that nearly half of these misfolded proteins can evade the cell's quality-control system entirely. The findings, published in the journal Nature Communications, suggest that such proteins can build up inside cells, disrupting the balance of protein production and recycling known as protein homeostasis, and potentially contributing to aging and disease.

As a cell makes a protein, the chain of amino acids folds into a working 3D shape; sometimes a loop forms in the chain and the string's end threads through it, creating a knot-like "entanglement." Misfolding can happen either when such an entanglement forms where it should not, or when one fails to form as part of the protein's natural structure. "We've recently identified a new class of protein misfolding, and we were interested in whether it had any impact on how the cellular quality control system maintains protein homeostasis," said Ed O'Brien, a professor of chemistry at Penn State's Eberly College of Science who led the research team.

Using an existing database of proteins tagged for degradation in human fibroblast cells, cross-referenced with a database of protein structures, the team found that proteins with a natural entanglement were 93% more likely to be tagged for removal than proteins without one, and that recently made proteins were often tagged even before they finished being built. Computer simulations showed that tagged proteins with an entanglement were four times more likely to misfold than untagged proteins without one — a result the researchers said suggests a failure to form the entanglement raises the chance a protein gets tagged for degradation.

Even so, about a third of proteins with an entanglement were not tagged for degradation despite their high rate of misfolding. "Sometimes a misfolded entanglement can be hidden deep within the structure of a protein, so that it isn't visible to the quality control system," said Yang Jiang, an associate research professor of chemistry at Penn State and the study's first author. Such proteins may evade degradation and persist in the cell despite being nonfunctional, the researchers said, potentially accumulating over time.