Interplay between hevin, SPARC, and MDGAs: modulators of neurexin-neuroligin trans-synaptic bridges

Hevin is secreted by astrocytes and its synaptogenic effects are antagonized by related protein, SPARC. Hevin stabilizes neurexin-neuroligin trans-synaptic bridges in vivo. A third protein, membrane-tethered MDGA, blocks these bridges. Here, we reveal the molecular underpinnings of a regulatory network formed by this trio of proteins. The hevin FS-EC structure differs from SPARC, in that the EC domain appears rearranged around a conserved core. The FS domain is structurally conserved and it houses nanomolar-affinity binding sites for neurexin and neuroligin. SPARC also binds neurexin and neuroligin, competing with hevin, so its antagonist action is rooted in its short N-terminal region. Strikingly, the hevin FS domain competes with MDGA for an overlapping binding site on neuroligin, while the hevin EC domain binds the extracellular matrix protein collagen (like SPARC), so that this trio of proteins can couple neurexin-neuroligin trans-synaptic bridges and the extracellular matrix, impacting synapse formation and ultimately neural circuits. Neuroligins and neurexins form trans-synaptic bridges that promote synapse development. Fan et al. reveal the molecular mechanism of hevin action, a secreted positive regulator of this trans-synaptic bridge, and unveil unexpected interplay with other regulators, SPARC and MDGA.