Archive for the ‘NLGN3/4’ Category

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Synaptic formation involves a complex series of steps including cellular movement, membrane specialization, molecular recognition, recruitment of pre- & postsynaptic docking proteins and accompanying receptors, reuptake & recycling factors. When individual components of this process are structurally unsound or misformed, it is easy to imagine that the process of synapse formation can go awry. To investigate this possibility, Fabrichny and colleagues evaluate the structure of key molecular complex that is known to influence the risk of autism spectrum disorder – a developmental disorder where synapse formation processes are known to be misregulated. In their paper, “Structural Analysis of the Synaptic Protein Neuroligin and Its b-Neurexin Complex: Determinants for Folding and Cell Adhesion”, (DOI) provide and in-depth x-ray structural assessment of a neuroligin (NLGN3/4) in complex with its target, beta-neurexin (NRXB1). This particular trans-synaptic molecular docking event is necessary for proper synapse formation and mutations in the neuroligin and neurexin genes appear to be associated with autism and mental retardation. One mutation associated with autism, Cys451Arg, is actually remote from the neurexin docking site, and rather causes problems by causing the neuroligin to get hung up in the endoplasmic reticulum. Another mutation, Gly99Ser, is located at the surface in a turn preceding the short b3 strand, and its mutation does not seem to affect folding or binding. As noted by the authors, Val403Met however, “participates in the tight parallel packing of the a2 helix onto the four-helix bundle and a mutation of this residue by a bulkier side chain may affect correct folding of the C-terminal domain and prevent formation of the functional neuroligin dimer.” This mutation then, unlike the other mutations, seems to play a more direct role in the structure of the docking event. Same disorder, same gene – different molecular mechanisms !

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