Scientists come closer to linking 'Jekyll and Hyde' protein with type 1 diabetes

Researchers have shown how a protein, called GAD65, changes its shape when it turns itself on and off and said that this characteristic could 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 Monash University, investigated how GAD65 regulates the production of neurotransmitters by changing its shape.

Principal Investigator Associate Professor Ashley Buckle said the findings showed that the normal function of the protein may come at a price.

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

Powerful beam lines at the Australian Synchrotron, as well as massive super computers at the Victorian Life Sciences Computation Initiative (VLSCI) and Monash, were used to accelerate the research.

The new research has been published in the journal PNAS.