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Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Nature Structural & Molecular Biology volume 15, pages 50–56 (2008)Cite this article

Abstract

The heterophilic synaptic adhesion molecules neuroligins and neurexins are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca2+-dependent and regulated by alternative splicing. We report a structure of the complex at a resolution of 2.4 Å between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin-1β (NX1β) LNS (laminin, neurexin and sex hormone–binding globulin–like) domain. The structure revealed a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca2+-mediated and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data supported a mechanism wherein splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1β interface. Mapping neuroligin mutations implicated in autism indicated that most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

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Figure 1: Structure of the NL1–NX1β complex.
Figure 2: The Ca2+ binding site in the NL1-NX1β complex.
Figure 3: The NL1-NX1β interface.
Figure 4: Alternative splice sites in the NL1–NX1β complex.
Figure 5: Autism-related neuroligin point mutations.

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Acknowledgements

We thank E.M. Silinsky for critically reading the manuscript and K.C. Garcia for encouragement. X.H. is supported by the Brain Tumor Society and US National Institutes of Health grant 1R01GM078055. The Structural Biology Facility is supported by the R.H. Lurie Comprehensive Cancer Center of Northwestern University. We thank the Southeast Regional Collaborative Access Team (SER-CAT) and Life Sciences Collaborative Access Team (LS-CAT) at the Advanced Photon Source, Argonne National Laboratory, for assistance in data collection.

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  1. Department of Molecular Pharmacology & Biological Chemistry, Northwestern University Feinberg School of Medicine, Searle 8-417, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    Xiaoyan Chen, Heli Liu, Ann H R Shim, Pamela J Focia & Xiaolin He

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X.C., H.L., A.H.R.S. and P.J.F. carried out experiments; X.H. supervised the research; X.C. and X.H. wrote the article.

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Correspondence to Xiaolin He.

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Chen, X., Liu, H., Shim, A. et al. Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. Nat Struct Mol Biol 15, 50–56 (2008). https://doi.org/10.1038/nsmb1350

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