Researchers have mapped the three-dimensional atomic structure of a two-part protein complex that plays a role in the signaling of chemicals known as neurotransmitters from brain cells.

A better understanding of how cells release these signals in less than a thousandth of a second could pave way for new research on drugs that could treat brain disorders.

Axel Brunger, from the Stanford School of Medicine and the SLAC National Accelerator Laboratory of the Department of Energy explained that the research could pave way for new drugs that control the release of neurotransmitter since many mental disorders such as anxiety, depression and schizophrenia affect the neurotransmitter systems.

Brunger, the senior author of the study publishing the findings in the journal Nature on Aug. 17, said that both parts of the two-piece protein complex have crucial roles but it was unclear how these structures called neuronal SNAREs and synaptotagmin-1 fit and work together.

X-ray studies conducted as early as two decades ago, have shown that SNARE proteins, which can be found in yeasts and mammalian cells, have a role in the chemical signaling of the brain.

In the new research, the researchers studied the joined protein structure by growing crystals of the complex and using a robotic system developed at SLAC's Stanford Synchrotron Radiation Lightsource (SSRL) for studying the crystals at an X-ray laser considered as one of the brightest sources of X-ray worldwide.

Researchers were able to reveal the atomic-scale details of the joined structure by combining and analyzing hundreds of X-ray images from around 150 protein crystals.

Brunger and colleagues discovered that when the SNAREs and synaptotagmin-1 join, they work like an amplifier causing a slight increase in the concentration of calcium, which triggers the release of neurotransmitters from one neuron to another.

The researchers also found that the proteins bind before they arrive at a neuron's membrane, which is why they can trigger brain signaling so fast. They think that several of the protein complexes that joined may group together and simultaneously interact with the same vesicle and this efficiently triggers the release of neurotransmitter.

"Here we report atomic-resolution crystal structures of Ca2+- and Mg2+-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains," the researchers reported.

James Rothman, from Yale University who discovered the SNARE proteins, said that the SNARE-synaptotagmin-1 complex structure is a milestone that has long been waited for and this sets the framework for an improved understanding of the system.

Photo: Allan Ajifo | Flickr

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