Research shows that how a protein called GAD65, changes its shape when it turns itself on and off. This characteristic may also link it to type-1 diabetes.

In the human brain, GAD65 performs an essential role- it makes ‘neurotransmitters’ - chemicals that pass messages between brain cells. GAD65 is also found in the pancreas.

Previous studies linked it to type-1 diabetes because the body makes antibodies against the protein.

However, the molecular details of what makes GAD65 ‘sticky’ to antibodies has remained a mystery until now.

The new research, led by Melbourne-based Monash University, investigated how GAD65 regulates the production of neurotransmitters by changing its shape.

The findings, published in the journal PNAS, showed that the normal function of the protein may come at a price, said Principal Investigator Ashley Buckle from the School of Biomedical sciences.

"GAD65 has an unpredictable, almost Jekyll and Hyde personality when it is turned on and off.    When active and making neurotransmitters, it is rigid and rather motionless," Buckle said.

"Ironically, when switched off, rather than resting as you might expect, it becomes mobile, dancing and jiggling around. We suspected that this dual personality might affect how antibodies 'see' it," he said.

"This turns out to be true - antibodies interact with it very differently depending on whether it's on or off," Buckle said.

GAD65 has previously been used in clinical trials as a vaccine for type-1 diabetes with limited success.

Buckle said the discovery may ultimately lead to the development of better vaccines to potentially treat and prevent type-1 diabetes.

"The idea to immunize an individual with GAD65 to help the immune system develop a tolerance against it, to stop or at least dampen the immune reaction is a good one. But so far these attempts have not been very successful. This research could change that," Buckle said.

The seven-year study used a combination of experimental and computational methods to understand what GAD65 looks like in its 'off' state and how human antibodies interact with both forms.


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