Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships.

Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses. HS directly binds postsynaptic partners neuroligins and LRRTMs, revealing a dual binding mode involving intrinsic glycan and protein domains for canonical synapse-organizing complexes. Neurexin HS chains also bind novel ligands, potentially expanding the neurexin interactome to hundreds of HS-binding proteins. Because HS structure is heterogeneous, our findings indicate an additional dimension to neurexin diversity, provide a molecular basis for fine-tuning synaptic function, and open therapeutic directions targeting glycan-binding motifs critical for brain development. Copyright © 2018 Elsevier Inc. All rights reserved.

Citation

Peng Zhang, Hong Lu, Rui T Peixoto, Mary K Pines, Yuan Ge, Shinichiro Oku, Tabrez J Siddiqui, Yicheng Xie, Wenlan Wu, Stephanie Archer-Hartmann, Keitaro Yoshida, Kenji F Tanaka, A Radu Aricescu, Parastoo Azadi, Michael D Gordon, Bernardo L Sabatini, Rachel O L Wong, Ann Marie Craig. Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships. Cell. 2018 Sep 06;174(6):1450-1464.e23

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PMID: 30100184

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