TY - JOUR
T1 - Interplay between hevin, SPARC, and MDGAs
T2 - Modulators of neurexin-neuroligin transsynaptic bridges
AU - Fan, Shanghua
AU - Gangwar, Shanti
AU - Machius, Mischa
AU - Rudenko, Gabby
N1 - Funding Information:
This work was funded by NIMH ( R01MH077303 ) and the Sealy Center for Structural Biology and Molecular Biophysics (SCSB) at UTMB. The Advanced Photon Source (IMCA-CAT, LS-CAT, and SBC-CAT) and the Advanced Light Source are thanked for access to synchrotron radiation.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - MDGAs
KW - SPARC
KW - adhesion molecule
KW - hevin
KW - matricellular protein
KW - neurexins
KW - neuroligins
KW - neuropsychiatric disease
KW - protein structure
KW - synaptic organizer
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U2 - 10.1016/j.str.2021.01.003
DO - 10.1016/j.str.2021.01.003
M3 - Article
C2 - 33535026
AN - SCOPUS:85101363064
SN - 0969-2126
VL - 29
SP - 664-678.e6
JO - Structure with Folding & design
JF - Structure with Folding & design
IS - 7
ER -