First Aid for Stressed Proteins

Scientists from University of Michigan and Göttingen (Germany) unravel how a versatile protein protects cells from oxygen damage. Published online in Molecular Cell.

Rather like a volunteer firefighter with a day job but who rushes to the rescue when the alarm is sounded, a cellular protein called GET3, switches roles to provide help when cell functions are threatened by oxidative stress, reports a team of University of Michigan and University of Göttingen (Germany) molecular biologists.

Their research, published online in Molecular Cell on September 22, 2014, solves the mystery of how cells survive oxidative stress despite the cell’s usual rescue service being incapacitated. The international research team was led by Ursula Jakob, Patricia S. Yaeger Professor of Molecular, Cellular, and Developmental Biology at the University of Michigan, and Professor Blanche Schwappach from the University of Göttingen (Germany).

Proteins consist of long chains of amino acids that must be folded into complex three-dimensional structures to be able to do their jobs in cells. Certain stresses, such as heat, can cause proteins to lose this precise structure and hence their activity. Rescue proteins, called chaperones, help a protein hold onto a protein in need of help, eventually assisting it to get back into its original shape. This cellular rescue service fails, however, when radical oxygen is involved.  This destructive form of oxygen is created when cells are exposed to UV irradiation, or by chemical substances such as those contained in cigarette smoke. The radicals deprive cells of their most important energy source--ATP molecules. Without ATP, the chaperones lack fuel for their work, and they therefore cannot keep damaged proteins from unfolding. Nevertheless, cells survive oxidative stress. The question that intrigued the researchers was “How do cells manage this?“

Oxidative stress transforms Get3 into a rescue protein

To answer this question, the scientists used yeast cells, which are especially suitable for genetic and biochemical studies and behave similarly to human cells. One strain of yeast cells lacks the Get3 protein. “Cells without Get3 have a remarkable defect,” says UM’s Ursula Jakob. “These cells are exceptionally sensitive to oxidative stress.” This observation puzzled scientists as there was no known connection between the role of Get3 in cells and the cellular defense against oxidative stress.

Normally, Get3 is responsible for anchoring certain proteins in cellular membranes. However, the researchers noted some intriguing similarities between Get3 and Hsp33, a protein that is present in bacteria.  “And Hsp33 is very important to protect bacteria from oxidative stress,” explains Wilhelm Voth, a visiting scholar from Göttingen in the Jakob lab.  “Hsp33 changes into a chaperone when it comes into contact with radical oxygen.”

Another clue was that Hsp33 does not depend on ATP to help proteins keep their shape. Hsp33 still works when the bacteria are facing oxidative stress and the conventional rescue service is out of fuel.  This suggested to the researchers that perhaps that Get3, as well, changes into an ATP-independent chaperone when oxygen radicals threaten cell proteins.

Indeed, the researchers found that Get3 fundamentally changes its folding when exposed to oxygen radicals. In this different shape, the Get3 can act as a chaperone to keep other proteins from losing shape, rendering “first aid” to other proteins under oxidative stress.  Just as firefighters work in teams, so too, the GET3 proteins join forces to rescue proteins. Four or more Get3 chaperones get together in a larger complex to take care of one damaged protein.

“The crucial thing, however, is that Get3 can switch back and forth between both shapes and functions,” stresses Blanche Schwappach from the University Medical Center Göttingen and the Göttingen Center for Molecular Biosciences (GZMB). “Hence, its transformation by radical oxygen is reversible.” Thus, the scientists report, Get3 belongs to an especially fascinating group of proteins. Over the course of evolution, these proteins took on a second job completely distinct from the first, and they can switch between the tasks as required.

“When cells suffer from oxidative stress, Get3 accordingly transforms into an ATP-independent chaperone and helps proteins damaged by oxygen. When the stress is over, it returns to its original task. For Get3, being a first-aid attendant appears to be its night job,” summarizes Professor Jakob. “Get3 transformation delivers the cell from the dilemma presented when oxidative stress causes the cell’s usual rescue service to run out of fuel.”

Voth et al., The Protein Targeting Factor Get3 Functions as ATP-Independent Chaperone under Oxidative Stress Conditions. Molecular Cell (2014),

Jakob Lab