Through a new approach of cross-linking cell proteins directly to a protein of interest, researchers at the University of Illinois Urbana-Champaign’s School of Molecular & Cellular Biology have distinguished new patterns of cell interactions with a molecular chaperone.
Molecular chaperones serve to support the health of all proteins, including the folding of nascent protein chains. By doing so, molecular chaperones ensure proteins are properly created and utilized before they’re dismantled at the ends of their lifespans. Thanks to their new approach of crosslinking cell proteins directly to their interaction partners, Professor Brian Freeman's lab in the Department of Cell & Developmental Biology has identified protein interaction features of the molecular chaperone called Hsp90.
The Freeman Lab’s research, published in Molecular Cell, showed that Hsp90 associated with roughly one-fifth of the yeast proteome using its three structural domains.
Intriguingly, the lab found that Hsp90 recognizes intrinsically disordered regions within target proteins, which serve as hubs for chaperone-binding. Scientists have long known about the existence of unstructured protein regions, but their perspectives on the role these regions play is shifting, said first author Janhavi Kolhe (PhD, cell and developmental biology, ’22).
“The idea was, for the longest time, that structure guides function,” Kolhe said. “Now we have all of these intrinsic disorders that were just thought to be linkers or not actually really having function, that can take up conformations depending on their environment, and they can also essentially serve as hubs for interaction.”
The Freeman Lab’s latest research could also have significant implications for treating cancer. In the past, researchers tried using Hsp90 as a therapeutic target in clinical trials for cancer. The trials all failed around the same point, during which the chaperone was inhibited. That prompted a heat shock response, allowing cancerous cells to retake lost ground.
“Previously it wasn’t known why inhibiting Hsp90 would cause a heat shock response,” Kolhe said. “Our hypothesis was that inhibiting Hsp90 essentially makes translation go a little haywire, and that results in a lot of aberrant proteins being generated. When they are generated or the translation machinery is affected, the cells automatically think of it as a stress response and upregulate chaperones in response to it.”
The Freeman Lab ultimately found that the heat shock response triggered by Hsp90 inhibition was dependent on active protein translation. The team is hopeful that their findings will help future therapeutic trials for cancers and pathogen infections move forward without triggering responses.