EBD Blog

Consistent with the theory that genetic variations cause Autism, there were two articles about proteins involved in neural synapses in the journal Neuron last month. I present the abstracts here primarily as a prompt for others to read them. These studies are pretty important because the proteins in question, the production of which is managed by genetic structures, moderate the activity of neurons and because these research teams are examining these actions at a very finite level.

I haven’t the time to go through them in detail and write an explication of each. However, I can start with a quick summary provide by Joshua Levinson and Alaa El-Husseini. Professors Levinson and El-Husseini provide a little context in their

Neuronal circuits are maintained by homeostatic mechanisms controlling synapse maturation and signaling. Neuroligins (NLs) and neurexins (Nrxs) may regulate the fine balance between excitation and inhibition. In this issue of Neuron, Araç et al. and Fabrichny et al. define crystal structures of NLs bound to β-Nrx, providing insights into their synaptic actions and clarifying structural defects associated with autism-linked mutations.

Here is the abstract for Fabrichny et al:

Structural Analysis of the Synaptic Protein Neuroligin and Its β-Neurexin Complex: Determinants for Folding and Cell Adhesion
Igor P. Fabrichny, Philippe Leone, Gerlind Sulzenbacher, Davide Comoletti, Meghan T. Miller, Palmer Taylor, Yves Bourne, and Pascale Marchot

The neuroligins are postsynaptic cell adhesion proteins whose associations with presynaptic neurexins participate in synaptogenesis. Mutations in the neuroligin and neurexin genes appear to be associated with autism and mental retardation. The crystal structure of a neuroligin reveals features not found in its catalytically active relatives, such as the fully hydrophobic interface forming the functional neuroligin dimer; the conformations of surface loops surrounding the vestigial active center; the location of determinants that are critical for folding and processing; and the absence of a macromolecular dipole and presence of an electronegative, hydrophilic surface for neurexin binding. The structure of a β-neurexin-neuroligin complex reveals the precise orientation of the bound neurexin and, despite a limited resolution, provides substantial information on the Ca2+-dependent interactions network involved in trans-synaptic neurexin-neuroligin association. These structures exemplify how an α/β-hydrolase fold varies in surface topography to confer adhesion properties and provide templates for analyzing abnormal processing or recognition events associated with autism.

Here is the abstract for Araç et al:

Structures of Neuroligin-1 and the Neuroligin-1/Neurexin-1β Complex Reveal Specific Protein-Protein and Protein-Ca2+ Interactions
Demet Araç, Antony A. Boucard, Engin Özkan, Pavel Strop, Evan Newell, Thomas C. Südhof, and Axel T. Brunger

The synaptic adhesion proteins neurexin and neuroligin, on the presynaptic and postsynaptic membranes, respectively, are involved in the assurance of proper synaptic function. Genetic mutations in neuroligins and neurexins have been linked to the genesis of autism and mental retardation. In two articles in this issue, Fabrinchy et al. and Araç et al. report high-resolution crystal structures of neuroligin alone and in complex with β-neurexin, unveiling the structural organization of these cell-adhesion proteins at the synaptic junction. These structures provide molecular insights into the role of the neuroligin/neurexin in synapse function by revealing the determinants critical for neuroligin processing at the synapse and for its transsynaptic association with neurexin. The structures also uncover how certain genetic mutations give rise to altered synaptic connectivity associated with autism spectrum disorders.

Abstract of Fabrichny et al. Abstract of Araç et al.
Link to a press release from the University of California San Diego about the Fabrichny et al. study. Link to the Brunger Lab from whence comes the Ara&cecdil; et al. study.