While the operation of chaperone proteins inside the cell is fairly well understood, how chaperones operate on proteins outside the cell is less well researched. Damaged and misfolded proteins exist outside the cell just as they exist inside the cell; consider amyloid-β aggregates in the context of Alzheimer's disease, for example. A greater understanding of extracellular chaperone proteins may enable novel strategies to target damaged and misfolded proteins characteristic of aging and disease, particularly in the brain.
A set of unique proteins - molecular chaperones - play an essential role in proteostasis: they target and interact with misfolded proteins, maintain their solubility, and designate them for refolding or degradation. And, while intracellular proteostasis is well understood, extracellular conditions are harsher. Mediating proteostasis in this environment requires specific extracellular molecular chaperones, and the specifics of extracellular proteostasis are yet to be fully understood. Take, for example, an extracellular chaperone, alpha 2-macroglobulin (ɑ2M), an abundant plasma protein. ɑ2M targets defective proteins and is speculated to facilitate the clearance of defective proteins. However, the exact mechanism of how this happens is unknown.
Now researchers have identified the substrates that ɑ2M targets for degradation. They also developed a novel assay that detects how ɑ2M mediates the lysosomal degradation of targeted proteins. The group also compared the substrate specificities of α2M and clusterin, another extracellular chaperone. Clusterin also plays a part in the extracellular degradation of proteins like amyloid-beta, the extracellular aggregation of which has been implicated in Alzheimer's disease. The group found that while α2M and clusterin had overlapping functions, their pathways were not redundant. α2M was seen to recognize the defective proteins more prone to aggregation. According to the researchers, this finding lends credence to the theory that an array of extracellular chaperones cooperates to protect us from the spectrum of misfolded proteins likely to be found in the body.
In the future, elucidating the molecular mechanism of protein degradation by extracellular chaperones may prove useful in treating related diseases, like Alzheimer's disease. By degrading and removing abnormal proteins that accumulate outside cells, extracellular chaperones have the potential to be a valuable therapeutic tool.