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...

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Vydáno v:	Cell Ročník 174; číslo 6; s. 1450
Hlavní autoři:	Zhang, Peng, Lu, Hong, Peixoto, Rui T, Pines, Mary K, Ge, Yuan, Oku, Shinichiro, Siddiqui, Tabrez J, Xie, Yicheng, Wu, Wenlan, Archer-Hartmann, Stephanie, Yoshida, Keitaro, Tanaka, Kenji F, Aricescu, A Radu, Azadi, Parastoo, Gordon, Michael D, Sabatini, Bernardo L, Wong, Rachel O L, Craig, Ann Marie
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 06.09.2018
Témata:	Amino Acid Sequence Animals Calcium-Binding Proteins Cell Adhesion Molecules, Neuronal - antagonists & inhibitors Cell Adhesion Molecules, Neuronal - genetics Cell Adhesion Molecules, Neuronal - metabolism Drosophila Drosophila Proteins - antagonists & inhibitors Drosophila Proteins - genetics Drosophila Proteins - metabolism Female Glycopeptides - analysis Heparitin Sulfate - chemistry Heparitin Sulfate - metabolism Humans Membrane Proteins Mice Mice, Inbred C57BL Nerve Tissue Proteins Neural Cell Adhesion Molecules - antagonists & inhibitors Neural Cell Adhesion Molecules - genetics Neural Cell Adhesion Molecules - metabolism Neurons - cytology Neurons - metabolism Protein Binding Rats RNA Interference RNA, Small Interfering - metabolism Sequence Alignment Synapses - metabolism LRRTM heparan sulphate synaptic transmission thorny excrescence mossy fiber synaptogenesis neurexin neuroligin proteoglycan synaptic adhesion protein
ISSN:	1097-4172, 1097-4172
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2018.07.002