Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Jan;15(1):50-6.
doi: 10.1038/nsmb1350. Epub 2007 Dec 16.

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Xiaoyan Chen  1 , Heli Liu, Ann H R Shim, Pamela J Focia, Xiaolin He
Affiliations

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Xiaoyan Chen et al. Nat Struct Mol Biol. 2008 Jan.

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 A between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin-1beta (NX1beta) 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-NX1beta 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Structure of the NL1-NX1β complex
(a) His-tag pulldown assay showing effects of mutagenesis of NX1β surface residues on NL1 binding. The gel is Coomassie-stained SDS-PAGE, with upper bands being His-tagged NL1 attached to Ni-NTA resin, and lower bands being non-His-tagged NX1β mutants retained by NL1. (b) The 2:2 NL1-NX1β complex in ribbons model, viewed from the direction of NX1β-localized membrane. NL1 is colored in orange and pink, NX1β in blue and cyan. Ca2+ ions are depicted as red balls. (c) The complex viewed from the side.
Figure 2
Figure 2. The Ca2+ binding site in the NL1-NX1β complex
(a) Coordination of the Ca2+ and its effect on NL1-NX1β interaction. NX1β is colored cyan, and NL1 colored pink. Ca2+ and waters are shown as red balls. Hydrogen bonds and Ca2+-oxygen interactions are shown as dashed red lines. Fo-Fc electron density calculated with the Ca2+ and waters omitted from the model is shown contoured at 4.5σ. The Ca2+ ion is octahedrally coordinated by four protein oxygen atoms from NX1β and two water molecules. WAT1 is bonded to both the Ca2+ and two NL1 oxygen atoms. The NX1β Asn238 sidechain is both bonded to the Ca2+ and to the NL1 mainchain. (b) Overlaying the structures of the Ca2+ bound to NX1β (Ca2+ as red ball and NX1β as cyan sticks) with the Ca2+ bound to NX1α-LNS2 (both Ca2+ and NX1α colored in orange) shows that the Ca2+ binding sites are in similar positions of the LNS domain. The major difference is that WAT1 in NX1β requires NL1 to be positioned, but the equivalent water in NX1α-LNS2’s structure can be positioned by the sidechain of Tyr412.
Figure 3
Figure 3. The NL1-NX1β interface
(a) Side view. NL1 and NX1β backbones are shown as coils. The sidechains of the important residues in NL1-NX1β interaction are shown as sticks. Waters and the Ca2+ are shown as red balls. The position of NX1β splice site 4 is shown as a cyan square, and is near the salt bridge between NL1 Asp387 and NX1β Arg232. (b) View from the NL1 direction. The position of NL1 splice site B is shown as a pink square, and is near the salt bridge between NL1 Glu297 and NX1β Arg109.
Figure 4
Figure 4. Alternative splice sites in the NL1-NX1β complex
(a) The locations of the NL1 sites, A and B, and NX1β SS#4 on the surface of the complex. Each residue immediately adjacent to the potential insert is colored green and shown in CPK representation. (b) Calorimetric titration between NL1 without the site B insert and NX1β. (c) Calorimetric titration between NL1 with the site B insert and NX1β. The NL1 protein does not have the site A insert and the NX1β protein does not have the SS#4 insert.
Figure 5
Figure 5. Autism-related neuroligin point mutations
The residues of mutations, NL1 Lys414 (corresponding to the NL4 K378R mutation), NL1 Arg473 (corresponding to the NL3 R451C mutation) and NL1 Val439 (corresponding to the NL4 V403M mutation), are colored in green and shown in CPK representation, and are mapped on the NL1-NX1β complex (ribbons). Note that these residues are away from the binding and dimerization interfaces, and are mostly buried.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Craig AM, Graf ER, Linhoff MW. How to build a central synapse: clues from cell culture. Trends Neurosci. 2006;29:8–20. - PMC - PubMed
    1. Chih B, Engelman H, Scheiffele P. Control of excitatory and inhibitory synapse formation by neuroligins. Science. 2005;307:1324–1328. - PubMed
    1. Chubykin AA, et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron. 2007;54:919–931. - PMC - PubMed
    1. Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell. 2004;119:1013–1026. - PMC - PubMed
    1. Scheiffele P, Fan J, Choih J, Fetter R, Serafini T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell. 2000;101:657–669. - PubMed

Publication types

MeSH terms

Associated data

-