A Splice Code for trans-Synaptic Cell Adhesion Mediated by Binding of Neuroligin 1 to α- and β-Neurexins

Boucard, Antony A.; Chubykin, Alexander A.; Comoletti, Davide; Taylor, Palmer; Südhof, Thomas C.

doi:10.1016/j.neuron.2005.08.026

Cited by 426 publications

(570 citation statements)

References 30 publications

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“…They bind to presynaptic alpha and beta forms of Neurexins (Ichtchenko et al, 1995(Ichtchenko et al, , 1996Missler et al, 1998;Boucard et al, 2005) and the alternative splicing of both protein families controls their binding affinities (Boucard et al, 2005;Chih et al, 2006;Comoletti et al, 2006;Fabrichny et al, 2007;Koehnke et al, 2008a,b;Shen et al, 2008). The current data suggest that Neurexin-Neuroligin binding is governed by a complex code that is based on the type of isoforms and splice variants involved, calcium binding, and glycosylation (Sudhof, 2008).…”

Section: Introductionmentioning

confidence: 60%

Characterization of the neuroligin gene family expression and evolution in zebrafish

Rissone¹,

Sangiorgio²,

Monopoli³

et al. 2010

Developmental Dynamics

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Neuroligins constitute a family of transmembrane proteins localized at the postsynaptic side of both excitatory and inhibitory synapses of the central nervous system. They are involved in synaptic function and maturation and recent studies have linked mutations in specific human Neuroligins to mental retardation and autism. We isolated the human Neuroligin homologs in Danio rerio. Next, we studied their gene structures and we reconstructed the evolution of the Neuroligin genes across vertebrate phyla. Using reverse-transcriptase polymerase chain reaction, we analyzed the expression and alternative splicing pattern of each gene during zebrafish embryonic development and in different adult organs. By in situ hybridization, we analyzed the temporal and spatial expression pattern during embryonic development and larval stages and we found that zebrafish Neuroligins are expressed throughout the nervous system. Globally, our results indicate that, during evolution, specific subfunctionalization events occurred within paralogous members of this gene family in zebrafish. Developmental Dynamics 239:688-702,

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Section: Introductionmentioning

confidence: 60%

Characterization of the neuroligin gene family expression and evolution in zebrafish

Rissone¹,

Sangiorgio²,

Monopoli³

et al. 2010

Developmental Dynamics

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“…4), each reduces binding by ~5 fold, further supporting that insert B acts though modulating the NL1 Glu297-NX1β salt bridge. Interestingly, the inhibitory effect of the NL1 site B insert appears to be augmented by the presence of the N-linked glycosylation in the middle of the insert residues 23 . This is perhaps because the N-linked glycan, with its large size, can restrain the conformation of the insert and adjacent residues, including Glu297, decreasing the possibility that NL1 Glu297 will achieve the conformation that allows salt bridge formation with NX1β Arg109.…”

Section: Effects Of Splice Sites On Nl1-nx1β Interactionmentioning

confidence: 99%

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Chen

Liu

Shim

et al. 2007

Nat Struct Mol Biol

147

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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 Ca 2+ -dependent and regulated by alternative splicing. We report a 2.4Å structure of the complex between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin 1β (NX1β) LNS (laminins, neurexins, and sex hormone-binding globulin-like) domain. The structure reveals a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca 2+ -mediated, and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data support a mechanism where 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 indicates most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

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“…The atomic structures of the second and sixth LNS domain of the NXα have recently been solved (12,13); however, no structural information on the arrangement of the entire extracellular domain is available. The inhibitory role of the glycosylation carried by splice insert B in NL1 was extensively studied in both NXα and NXβ (14,15). More recently it was established that splice insert B has an even larger effect on the association than glycosylation alone (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the solution structure of a neuroligin/β-neurexin complex

Comoletti

Grishaev

Whitten

et al. 2008

Chemico-Biological Interactions

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SUMMARYNeuroligins are postsynaptic cell adhesion molecules that promote synaptic maturation and stabilization upon binding with presynaptic partners, the α-and β-neurexins. Using a combination of analytical ultracentrifugation, small angle x-ray, and neutron scattering, we have characterized the low-resolution three-dimensional structure of the extracellular domain of the neuroligins, free in solution, and in complex with β-neurexin. The globular extracellular domain of the neuroligins forms stable homodimers through a four-helix bundle typical of the cholinesterases and other members of the α/β-hydrolase fold family. The presence of the stalk region adds to the extracellular domain of neuroligin-1 an elongated structure, suggesting a rod-like nature of the stalk domain. Sedimentation equilibrium coupled with solution scattering data of the β-neurexin/neuroligin-1 complex indicated a 2:2 stoichiometry where two β-neurexin molecules bind to a neuroligin-1 dimer. Deuteration of neurexin allowed us to collect neutron scattering data that, in combination with other biochemical techniques, provide a basis for optimizing the positioning of each component in a higher resolution computational model of the neuroligin/neurexin complex. As several mutations of both neurexin and neuroligin genes have been linked to autism spectrum disorders and mental retardation, these new structures provide an important framework for the study of altered structure and function of these synaptic proteins.

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A Splice Code for trans-Synaptic Cell Adhesion Mediated by Binding of Neuroligin 1 to α- and β-Neurexins

Cited by 426 publications

References 30 publications

Characterization of the neuroligin gene family expression and evolution in zebrafish

Characterization of the neuroligin gene family expression and evolution in zebrafish

Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Characterization of the solution structure of a neuroligin/β-neurexin complex

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