Cells produce bad proteins all the time, and in large-enough numbers, these molecules can spell danger for the body. When misfolded or unfolded, proteins can't do their jobs. At worst, they harm cells by clumping into the sticky plaques that are the signatures for neurodegenerative disorders such as Alzheimer's disease.
A clear understanding of how most cells successfully manage protein repair and disposal has been elusive. But now, research has unmasked one of the molecular participants in the process. In the January Nature Cell Biology, scientists studying gene expression in failing hearts report the function of an important molecular player in the cell's quality-control system.
Called CHIP (carboxyl terminus of Hsc70-interacting protein), this molecule decides the fate of malformed proteins in heart muscle, says Cam Patterson of the University of North Carolina at Chapel Hill. CHIP judges whether to slate bad proteins for repair or destruction, he says.
The findings may help researchers piece together the puzzle of protein regulation and lead to a new generation of therapies for heart disease and nervous system disorders, says Patterson.
The process of protein sorting has been dubbed triage for its similarity to the way that medical personnel sort patients in emergency rooms. Proteins exist in the cell in three different states: functional, misfolded or unfolded but salvageable, and beyond all hope.
During protein triage, the refolding molecules, called chaperones, recognize misfolded peptides and tidy them up (SN: 9/6/97, p. 155). Another cellular molecule, a proteasome, breaks apart those protein candidates that are beyond fixing. Until now, however, there's been no direct link between the molecules charged with fixing the folding and those that destroy proteins.
Hearts under stress are loaded with both damaged proteins and molecules that refold proteins. Patterson and his colleagues discovered that CHIP's abundance in the heart also increases during stress. The group then suspected that CHIP is the triage arbiter.
During triage, CHIP steps in and binds to a chaperone that's holding a badly misshapen protein, preventing any refolding, the team reports. Instead, CHIP shuttles the reject to the proteasome, which destroys it.
"What's interesting about [CHIP] is it seems to have two different functional units that are linked together," says Judith Frydman, who studies protein folding at Stanford University. One unit binds CHIP to a chaperone, and the other presents the protein to the proteasome.
CHIP, Patterson asserts, represents a major pathway for degrading spoiled protein and keeping the cell on track making good protein. "The balance seems to be a yin-yang situation," he says.
"We have known more about the yin–when to refold proteins. Now, we're trying to learn about the yang–understanding when they are discarded and why.
"We have thought that the cells would have a powerful means for clearing out [hopelessly damaged proteins], a cellular garbage can," says Patterson. He and his colleagues suggest that a chemical resembling CHIP could be used as a drug to clear away damaged proteins in the heart and other organs.
"I think this is really an exciting paper because for the first time it links . . . protein folding and protein degradation," says Marschall Runge, a cardiovascular researcher also at the University of North Carolina. These two areas are critical during a heart attack, and a better understanding of their linkage will open up a new area for development of therapeutic strategies, he says.
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Meacham, G.C., et al. 2001. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature Cell Biology 3(January):100.
Strauss, E. 1997. How proteins take shape. Science News 152(Sept. 6):155.
Wickner, S., M.R. Maurizi, and S. Gottesman. 1999. Posttranslational quality control: Folding, refolding, and degrading proteins. Science 286(Dec. 3):1888.