Researcher finds possible way to unravel misfolded proteins by reprogramming yeast protein

Published on January 17, 2014 at 5:47 AM · No Comments

Shorter identified Hsp104's coiled-coil middle domain as a major area affecting its ability to function as a chaperone, noting that minor mutations in this domain appear to have wide-ranging potential to unlock the molecule's protein clump-busting capabilities. He suggests that the middle domain of Hsp104 functions much like an electrical capacitor, storing the protein's beneficial possibilities. A seemingly small tweak of the middle-domain structure, as well as other parts of the molecule such as the pore loops, can unleash a surprising therapeutic power.

With that power now demonstrated in the relatively primitive worm species, the team's next step will be to move to a more complex animal model in mice, where the side effects of introducing a foreign protein into an organism might be a concern.

Shorter explains that aside from Hsp104's declumping function, "the other major goal from a bioengineering viewpoint is to make the tweaked Hsp104 specific in what it targets because all the variants we have at the moment seem to work across the board. That's not what you want for a therapeutic, because there might be off-target effects."

He stresses that although his protein reengineering approach is not yet a cure or practical treatment for neurodegenerative disease, it's a major first step toward that ultimate goal and shows that clump busting -- what was previously thought impossible -- is within reach, adding, "We've defined that it is possible to achieve clot-busting activity in a simple model system. The challenge is to move it forward from there."

SOURCE Penn Medicine

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