This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: As proteins are made in a cell, they are folded into the 3D structure that allows them to work, but sometimes this process can go wrong. When it does, the misfolded proteins lose some or all of their function and usually get tagged by the cell's quality assurance and maintenance crews, which try to repair the proteins or, if they can't, strip them to recycle their parts.
A new study led by scientists at Penn State revealed that proteins containing a certain type of structure are more likely to misfold and be targeted for removal, yet nearly half still manage to evade the cellular maintenance crew. The misfolded proteins that persist could accumulate in cells, disrupting the balance of protein production and recycling and potentially contributing to aging and disease, according to the researchers. The study was recently published in Nature Communications.
"Like a tiny factory, cells make proteins," said Ed O'Brien, professor of chemistry in the Penn State Eberly College of Science and the leader of the research team. "And like a factory, cells have quality control mechanisms to catch any errors on the production line. 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 a balance of protein production, repair and recycling—protein homeostasis.
"Additionally, protein misfolding is known to contribute to diseases like Alzheimer's and Huntington's. Therefore, increasing our understanding of the basic biology underlying this novel class of misfolding could lead to the identification of new disease origins and treatments." The new class of misfolding occurs through a change in the entanglement of a segment of the protein. The string of amino acids that make proteins can form a loop, and the end of the string can thread through the loop, forming a knot-like structure.
Misfolding can occur either by this type of entanglement forming where it shouldn't or by failing to form when it is part of a protein's natural structure. "We focused on proteins that have an entanglement as part of their native structure because we have shown in the past that they are more likely to misfold," said Yang Jiang, associate research professor of chemistry at Penn State and first author of the paper. "We used an existing database of proteins that have been tagged with a marker for degradation in human fibroblast cells and cross-referenced it with a database of protein structures so we could see the proportion of proteins with the entanglement that were marked by the cellular quality control mechanism." Repurposing publicly available data to answer new biological questions is the central mission of the U.S.
National Science Foundation (NSF) National Synthesis Center for Emergence in the Molecular and Cellular Sciences (NCEMS) at Penn State. This center brings teams of scientists together to reuse and gain deeper insights from existing datasets without the need to conduct new experiments. "In science, we often collect massive amounts of data to answer the specific questions that we are interested in, and then that data sits unused," said O'Brien, who is director of NCEMS.
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