A ternary Neurexin-T178-PTPR complex represents a core-module of neuronal synapse organization

Complexes of synaptic adhesion molecules instruct the formation, functional specification and plasticity of neuronal synapses. Proteomic and candidate gene studies have identified an array of synaptic adhesion molecules that may cooperate or provide independent columns connecting synaptic compartments, thereby, promoting the nucleation of presynaptic active zones and recruitment of postsynaptic neurotransmitter receptors.

Here, we used a systematic large-scale multi-epitope affinity-purification approach (total of >120 purifications with 30 target proteins), combined with quantitative mass spectrometry to comprehensively map trans-synaptic protein networks in the mouse brain. We discover a universal presynaptic core-module consisting of the neurexin proteins and LAR-type receptor protein tyrosine phosphatases (PTPRD,S,F), linked by the tetraspanin proteins T178A, B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B results in module dissociation and loss of LAR-PTPRs. At synapses, the Neurexin-T178-PTPR module recruits stable trans-synaptic protein networks with specific pre- and post-synaptic partners and secreted extracellular linkers. These networks encompass stable associations with unique postsynaptic GABAergic and glutamatergic neurotransmitter receptor complexes, identifying the Neurexin-T178-PTPR module as a central, universal integrator of trans-synaptic signaling in the central nervous system.