NRXs interact intracellularly with CASK and Mint PDZ domain proteins and the synaptic vesicle protein synaptotagmin α-NRXs also functionally link to presynaptic voltage-gated Ca 2+ channels ( Reissner et al., 2013). NLs recruit ionotropic glutamate and GABA A receptors through direct interactions or using DLG (Discs large) family or gephyrin and collybistin accessory proteins, respectively ( Bemben et al., 2015). The NL-NRX complexes promote synaptic cell adhesion via direct extracellular interactions and recruit the molecular machinery for neurotransmitter release and reception. Members of the presynaptic neurexin (NRX) and postsynaptic neuroligin (NL) transmembrane protein families form the axis of a signaling pathway that is crucial for the formation and function of excitatory and inhibitory synapses throughout the brain ( Südhof, 2008). These results illustrate a potentially brain-wide regulatory mechanism for NL-NRX signaling modulation.Ĭell-surface synaptic organizing proteins play a central role in the assembly, maturation, stabilization, and plasticity of neuronal synapses ( Siddiqui and Craig, 2011).
We demonstrate that expression levels largely determine whether MDGAs act selectively or suppress the synapse organizing function of multiple NLs. Structural analyses guided the discovery of a broad, splicing-modulated interaction network between MDGA and NL family members and helped rationalize the impact of autism-linked mutations. Two large, multi-domain MDGA molecules fold into rigid triangular structures, cradling a dimeric NL to prevent NRX binding. Here, we report crystal structures of MDGA1, the NL1-MDGA1 complex, and a spliced NL1 isoform. MDGA proteins bind NLs and control their function and interaction with NRXs via unknown mechanisms. An accurate spatial and temporal control of NL-NRX signaling is crucial to balance excitatory and inhibitory neurotransmission, and perturbations are linked with neurodevelopmental and psychiatric disorders.
Neuroligin-neurexin (NL-NRX) complexes are fundamental synaptic organizers in the central nervous system.
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