Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges

Gangwar, Shanti Pal; Zhong, Xiaoying; Seshadrinathan, Suchithra; Chen, Hui; Machius, Mischa; Rudenko, Gabby

doi:10.1016/j.neuron.2017.06.009

Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges

Journal Article · Wed Jun 21 00:00:00 EDT 2017 · Neuron

DOI:https://doi.org/10.1016/j.neuron.2017.06.009· OSTI ID:1439611

Gangwar, Shanti Pal ^[1]; Zhong, Xiaoying ^[1]; Seshadrinathan, Suchithra ^[1]; Chen, Hui ^[2]; Machius, Mischa ^[1]; Rudenko, Gabby ^[1]

Univ. of Texas Medical Branch, Galveston, TX (United States)
Univ. of Michigan, Ann Arbor, MI (United States)

Neuroligins and neurexins promote synapse development and validation by forming trans-synaptic bridges spanning the synaptic cleft. Select pairs promote excitatory and inhibitory synapses, with neuroligin 2 (NLGN2) limited to inhibitory synapses and neuroligin 1 (NLGN1) dominating at excitatory synapses. The cell-surface molecules, MAM domain-containing glycosylphosphatidylinositol anchor 1 (MDGA1) and 2 (MDGA2), regulate trans-synaptic adhesion between neurexins and neuroligins, impacting NLGN2 and NLGN1, respectively. In our work, we have determined the molecular mechanism of MDGA action. MDGA1 Ig1-Ig2 is sufficient to bind NLGN2 with nanomolar affinity; its crystal structure reveals an unusual locked rod-shaped array. In the crystal structure of the complex, two MDGA1 Ig1-Ig2 molecules each span the entire NLGN2 dimer. Site-directed mutagenesis confirms the observed interaction interface. Strikingly, Ig1 from MDGA1 binds to the same region on NLGN2 as neurexins do. Thus, MDGAs regulate the formation of neuroligin-neurexin trans-synaptic bridges by sterically blocking access of neurexins to neuroligins.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Brain and Behavior Research Foundation; National Institute of Mental Health (NIMH); USDOE Office of Science (SC); UT BRAIN Award

OSTI ID:: 1439611

Journal Information:: Neuron, Journal Name: Neuron Journal Issue: 6 Vol. 94; ISSN 0896-6273

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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