Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges

Shanghua Fan, Shanti Pal Gangwar, Mischa Machius, Gabby Rudenko

Research output: Contribution to journalArticlepeer-review


Hevin is secreted by astrocytes and its synaptogenic effects are antagonized by the related protein, SPARC. Hevin stabilizes neurexin-neuroligin transsynaptic 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 shortened 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 regulate neurexin-neuroligin transsynaptic bridges and also extracellular matrix interactions, impacting synapse formation and ultimately neural circuits.

Original languageEnglish (US)
Pages (from-to)664-678.e6
Issue number7
StatePublished - Jul 1 2021


  • MDGAs
  • adhesion molecule
  • hevin
  • matricellular protein
  • neurexins
  • neuroligins
  • neuropsychiatric disease
  • protein structure
  • synaptic organizer

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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