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When newly created proteins emerge from the cell’s protein-making machinery, they appear as useless, spaghetti-like strands. Only after these strands fold into their intricate, final globular shapes can proteins begin their work as enzymes and other essential cellular components.
Linda Hendershot, PhD, Genetics and Tumor Cell Biology, and her colleagues study the critical chaperone proteins that shepherd this folding. The chaperones ensure the proteins fold properly and eject those that do not by sending them to the cell’s protein-disposal machinery.
These chaperones are so crucial to life that they appear in every cell of every creature from bacteria to humans, aiding every biological process. Protein-folding malfunction plays a role in a vast array of disorders, including cystic fibrosis, Huntington’s disease, several neurodegenerative and lysosomal storage diseases, and Alzheimer’s disease. Genetic mutations in the chaperones have also been found to cause such genetics disorders as polycystic kidney disease and a hereditary form of ataxia known as Marinesco-Sjögren syndrome. Basic understanding of protein-folding could lead to important insights into such disorders.
In a study published in the November 5, 2008, issue of The EMBO Journal, Hendershot and her colleagues explore the role of a chaperone called BiP and a co-chaperone called ERdj3. These two proteins reside in the endoplasmic reticulum, which is a major site of protein synthesis. To guide protein folding, ERdj3 first recognizes and latches onto a newly formed protein and attracts BiP, which then clamps onto the protein. ERdj3 then detaches itself, moving on to its next protein target.
“A lot is known about how chaperones like BiP are recruited to proteins; how they bind to them; and how they are released,” said Hendershot, the paper’s senior author. “But what has been a mystery was how important co-chaperones like ERdj3 hand the unfolded protein to BiP and leave.”
One theory was that the two molecules merely compete for a spot on the target protein, with BiP winning the shoving match and ejecting ERdj3. Another theory was that when ERdj3 triggers the newly arrived BiP molecule to snap shut onto the target protein, a reciprocal signal would be generated to release ERdj3.
To discover the actual mechanism, Hendershot and her colleagues created mutant forms of both BiP and ERdj3 that were defective in their ability to carry out interactions with each other and with unfolded proteins and other functions. The investigators then observed how the mutants affected the molecular dance of ERdj3, BiP and a target protein.
The experiments revealed that ERdj3 and BiP did not compete for space on the target protein, but rather coexisted. The studies also demonstrated that ERdj3 triggers BiP to activate the energy-storage molecule called ATP to power the action of snapping shut around the protein. Only then does ERdj3 depart.
“The findings are significant because they lead to a model that is appealing to biologists because it shows a precise degree of control over this critical process,” Hendershot said. “This model holds that ERdj3’s job is not only to recruit BiP and catalyze the process, but also to monitor it to ensure that it occurs properly. This is an exquisite way to regulate this system because it makes sure that the chaperone comes in and engages the protein before the co-chaperone leaves; and it really allows this handoff to happen as flawlessly as possible.”
Since the chaperone machinery is standardized in all organisms, the departure mechanism discovered for ERdj3 and BiP likely extends throughout other chaperone pairs in biology, Hendershot said.
In further studies, the researchers will explore the function of other co-chaperones like ERdj4 and ERdj5, which play a role in other cellular processes involving protein-folding. For example, some co-chaperones help unfold malformed proteins so they can be sent to the cell’s protein-shredding disposal machinery. Important questions include not only how the disposal co-chaperones work, but how they receive the defective proteins in a hand-off from other co-chaperones. Such a handoff system has to work efficiently for the cell to avoid being poisoned by defective proteins.
“It’s like the quality-control system in a factory, where you have to identify the components that don’t work right and get them off the conveyor belt very quickly,” Hendershot said.
Other authors of this paper include Yi Jin and Walid Awad, MD, both of Genetics and Tumor Cell Biology.
This research was supported in part by the National Institutes of Health, a Cancer Center CORE grant and ALSAC.