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

Structure. 2021 Jul 1;29(7):664-678.e6. doi: 10.1016/j.str.2021.01.003. Epub 2021 Feb 2.


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.

Keywords: MDGAs; SPARC; adhesion molecule; hevin; matricellular protein; neurexins; neuroligins; neuropsychiatric disease; protein structure; synaptic organizer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Calcium-Binding Proteins / chemistry*
  • Calcium-Binding Proteins / metabolism*
  • Crystallography, X-Ray
  • Extracellular Matrix Proteins / chemistry*
  • Extracellular Matrix Proteins / metabolism*
  • Humans
  • Models, Molecular
  • Nerve Tissue Proteins / metabolism*
  • Neural Cell Adhesion Molecules / metabolism*
  • Osteonectin / chemistry*
  • Osteonectin / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Protein Interaction Maps


  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecules
  • Osteonectin
  • SPARC protein, human
  • SPARCL1 protein, human