Abstract
Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) function as postsynaptic organizers that induce excitatory synapses. Neurexins (Nrxns) and heparan sulfate proteoglycans have been identified as presynaptic ligands for LRRTMs. Specifically, LRRTM1 and LRRTM2 bind to the Nrxn splice variant lacking an insert at the splice site 4 (S4). Here, we report the crystal structure of the Nrxn1β–LRRTM2 complex at 3.4 Å resolution. The Nrxn1β–LRRTM2 interface involves Ca2+-mediated interactions and overlaps with the Nrxn–neuroligin interface. Together with structure-based mutational analyses at the molecular and cellular levels, the present structural analysis unveils the mechanism of selective binding between Nrxn and LRRTM1/2 and its modulation by the S4 insertion of Nrxn.
Highlights
Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) function as postsynaptic organizers that induce excitatory synapses
The structure of engineered mouse LRRTM2 leucine-rich repeat (LRR) has been reported, 33% of the residues were mutated to enhance the thermostability of the protein[18]
The N157A mutation may affect the Ca2+ coordination by Val[158] in this loop. In addition to these 5 critical mutations, 7 other mutations reduced the binding to ~40% of wild-type levels. These residues are located around the interface between Nrxn1β and LRRTM2, none of them are directly involved in the Nrxn1β–LRRTM2 interaction
Summary
Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) function as postsynaptic organizers that induce excitatory synapses. Neurexins (Nrxns) are a representative presynaptic organizer family and interact with several different postsynaptic organizers such as neuroligins (NLs), Cbln1–GluD2, and leucine-rich repeat transmembrane neuronal proteins (LRRTMs)[2,3,4,5,6]. Previous cell-surface binding assays suggested that LRRTMs bind to Nrxn (–S4)[6,10]. LRRTMs are potent postsynaptic organizers that have been shown to instruct presynaptic differentiation[12]. The isolated extracellular region of LRRTMs can instruct excitatory presynaptic differentiation[12]. Together with structureguided mutational studies by SPR analyses and fibroblast–neuron co-culture assays, the present structures elucidate the mechanism of the –S4-dependent Nrxn–LRRTM interaction and selective binding of Nrxn1β to LRRTM1 and LRRTM2
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