Researchers have unveiled the structure of a key protein complex implicated in brain disorders such as autism
Researchers in France and the US have caught on camera the gentle embrace between two proteins that sit on either side of the junction between nerve cells. The proteins form a loose but crucial bridge across the junction, the synapse, and their malfunction has been implicated in certain types of autism - a disorder of the brain that impairs social interaction and communication.
The new work sheds important light on the precise molecular organisation of the synapse which could, ultimately, identify potential sites for drug targets.
Igor Fabrichny, from the University of Marseilles in France, and colleagues, fully resolved the crystal structure of one of the proteins, neuroligin, and also the structure of the complex of neuroligin bound to its partner,
’These proteins meet together in the early development of the brain and in some autistic patients there are mutations in the proteins,’ team member Pascale Marchot told Chemistry World. ’It seems that certain mutations result in these proteins being unable to associate together, causing malfunctioning of the synapse.’
Intriguingly neuroligin belongs to a family of proteins that are almost exclusively enzymes - such as acetylcholinesterase. Neuroligin, however, has no catalytic activity. What it does possess is an unusual area of electronegativity upon its surface. ’This differentiates the protein from its structurally similar enzyme cousins and also seems to play a part in allowing it to recognise its partner neurexin,’
Marchot said. ’This area of electronegativity corresponds exactly to the position of binding. It could also explain why other proteins of the family are not able to recognise neurexin.’ Mutations in either neuroligin or neurexin can cause a slight but devastating rearrangement of the amino acid sequence which affects the way the proteins fold, preventing them from sticking together.
’I believe this work will help us understand better how these two proteins behave, what is necessary to make them fold correctly and recognise each other,’ Marchot said.
The researchers were not able to see the structure of the two-protein complex in great detail but they are confident that they have correctly identified the amino acid side-chains at the interface of the complex.
The complex of the two proteins is known to form only when calcium ions are present. The team found a calcium ion bound at the interface between the two proteins but say that they will also need better data to fully describe how the calcium ion is coordinated and why calcium - rather than other cations - is necessary for the proteins to bind to each other.
Commenting on the study, structural biologist David Stuart of the University of Oxford, UK, said, ’Fabrichny et al have used [x-ray crystallography] to reveal how two proteins that form key interactions responsible for the formation of neural synapses, and are implicated in disorders including autism, recognize each other. This work epitomises the current efforts to apply structural biology to dissect the organisation of cells and inter-cellular interactions in atomic detail.’
I P Fabrichny et al, Neuron, 2007, DOI: 10.1016/j.neuron.2007.11.013