Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins

Elegheert, J.; Cvetkovska, Vedrana; Clayton, Amber J.; Heroven, Christina; Vennekens, Kristel M.; Smukowski, Samuel N.; Regan, Michael C.; Jia, Wanyi; Smith, Alexandra C.; Furukawa, Hiro; Savas, Jeffrey N.; Wit, Joris de; Begbie, Jo; Craig, Ann Marie; Aricescu, A. Radu

doi:10.1016/j.neuron.2017.09.011

Cited by 32 publications

(46 citation statements)

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“…Interestingly, olfactomedin-1, which was not identified in Schwann cell secretomes, is known to interact with NOGO-A receptor complex, an axon repulsion complex (45). In addition, proteins involved in synaptic organization [e.g., tissue-type plasminogen activator (46), neurexin and neuroligin (47,48)] were identified. Another important protein in the context of nerve repair is reelin because it was shown to regulate Schwann cell/axon interactions (49).…”

Section: Composition Of Schwann Cell Secretomesmentioning

confidence: 99%

Secretome analysis of nerve repair mediating Schwann cells reveals Smad‐dependent trophism

et al. 2018

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Schwann cells promote nerve regeneration by adaptation of a regenerative phenotype referred to as repair mediating Schwann cell. Down‐regulation of myelin proteins, myelin clearance, formation of Bungner's bands, and secretion of trophic factors characterize this cell type. We have previously shown that the sphingosine‐1‐phosphate receptor agonist Fingolimod/FTY720P promotes the generation of this particular Schwann cell phenotype by activation of dedifferentiation markers and concomitant release of trophic factors resulting in enhanced neurite growth of dorsal root ganglion neurons. Despite its biomedical relevance, a detailed characterization of the corresponding Schwann cell secretóme is lacking, and the impact of FTY720P on enhancing neurite growth is not defined. Here, we applied a label‐free quantitative mass spectrometry approach to characterize the secretomes derived from primary neonatal and adult rat Schwann cells in response to FTY720P. We identified a large proportion of secreted proteins with a high overlap between the neonatal and adult Schwann cells, which can be associated with biologic processes such as development, axon growth, and regeneration. Moreover, FTY720P‐treated Schwann cells release proteins downstream of Smad signaling known to support neurite growth. Our results therefore uncover a network of trophic factors involved in glial‐mediated repair of the peripheral nervous system.—Schira, J., Heinen, A., Poschmann, G., Ziegler, B., Hartung, H.‐P., Stühler, K., Küry, P. Secretome analysis of nerve repair mediating Schwann cells reveals Smad‐dependent trophism. FASEB J. 33, 4703–4715 (2019). http://www.fasebj.org

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Section: Composition Of Schwann Cell Secretomesmentioning

confidence: 99%

Secretome analysis of nerve repair mediating Schwann cells reveals Smad‐dependent trophism

et al. 2018

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“…Gli is part of Neuroligin family [45], a set of proteins involved in synapse formations [46] and synaptic transmission [47,48]. Moreover, recent studies highlighted physical interaction between MGDA proteins and Neuroligin [49][50][51]. MGDA proteins are composed of six N-terminal Ig domains and one fibronectin type III domain [52], which looks like Nrg organization, displaying also six N-terminal Ig domains followed by five fibronectin type III domain [53].…”

Section: Tsj Role On Sj Integritymentioning

confidence: 99%

“…MGDA proteins are composed of six N-terminal Ig domains and one fibronectin type III domain [52], which looks like Nrg organization, displaying also six N-terminal Ig domains followed by five fibronectin type III domain [53]. MGDA are reported interacting with Neuroligin via their first two Ig domains [49][50][51]. Based on our results and knowing that Nrg formed a complex with Cora, ATP-α and Nrx-IV [6,10], the link between tSJ and SJ could be Gli binding Nrg.…”

Section: Tsj Role On Sj Integritymentioning

confidence: 99%

Interplay between Anakonda, Gliotactin and M6 for tricellular junction assembly and anchoring of septate junctions inDrosophilaepithelium

Bournonville

Borgne

2020

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In epithelia, Tricellular junctions (TCJs) serve as pivotal sites for barrier function and integration of both biochemical and mechanical signals. While essential for tissue homeostasis, TCJ assembly, composition and links to adjacent bicellular junctions (BCJs) remain poorly understood. Here we have characterized the assembly of TCJs within the plane of adherens junctions (tAJ) and the plane of septate junctions (tSJ) in Drosophila and report that their formation is spatiotemporally decoupled. The assembly and stabilization of previously described tSJ components Anakonda (Aka) and Gliotactin (Gli) as well as the newly reported tSJ proteolipid protein M6, is shown to be a complex process. Aka and M6, whose localization is interdependent, act upstream to locate Gli. In turn, Gli stabilizes Aka at tSJ. Those results unravel a previous unknown role of M6 at tSJ and a tight interplay between tSJ components to assemble and maintain tSJs. In addition, tSJ components are not only essential at vertex as we found that loss of tSJ integrity also induces micron-length bicellular SJs deformations that are free of tensile forces. This phenotype is associated with the disappearance of SJ components at tricellular contacts, indicating that bSJ are no longer connected to tSJs. Reciprocally, SJ components are in turn required to restrict the localization of Aka and Gli at vertex. We propose that tSJs function as pillars to anchor bSJs to ensure the maintenance of tissue integrity in Drosophila proliferative epithelia. Introduction:

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“…The effects of alternative splicing on the neurexophilin-neurexin interaction contrast with previous findings for a related synaptic protein interface. While LNS2 domains with SS2 inserts show higher affinity for Nxph1 than insert-free LNS2, the opposite is true for neurexin-neuroligin interactions, where Nrxn1b with a 30-amino acid insert in SS4 (b-Nrxn1 SS4+ ) has a lower affinity for neuroligins than b-Nrxn1 SS4À (Boucard et al, 2005;Elegheert et al, 2017;Fig 6). In this case, the SS4 insert functions differently than SS2 inserts; the SS4 insert likely sterically interferes with binding of neuroligin to b-Nrxn1 SS4+ (Shen et al, 2008), whereas LNS2 with SS2A insertsand likely SS2AB inserts-form additional interactions with Nxph1 not found between Nxph1 and LNS2 SS2À .…”

Section: Effects Of Alternative Splicingmentioning

confidence: 99%

“…While alternative splicing of neurexins has dramatic effects on their interactions with ligands (Südhof, 2017), no structural data explain how alternative splicing regulates these interactions at the atomic level. For example, Nrxn1b lacking an insert in SS4 has a higher binding affinity for neuroligin-1 (Nlgn1) than Nrxn1b containing an insert in SS4 (Boucard et al, 2005;Comoletti et al, 2006;Shen et al, 2008;Elegheert et al, 2017), but the structural basis for this regulatory effect is unknown. The structure of the Nlgn1-Nrxn1b complex lacking the SS4 splice insert has been determined (Araç et al, 2007;Tanaka et al, 2011), but no structure is available for the Nlgn1-Nrxn1b complex containing the SS4 insert, even though most neuroligins bind to Nrxn1b containing an SS4 insert, albeit with a lower affinity.…”

Section: Introductionmentioning

confidence: 99%

Structures of neurexophilin–neurexin complexes reveal a regulatory mechanism of alternative splicing

et al. 2019

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Neurexins are presynaptic, cell‐adhesion molecules that specify the functional properties of synapses via interactions with trans‐synaptic ligands. Neurexins are extensively alternatively spliced at six canonical sites that regulate multifarious ligand interactions, but the structural mechanisms underlying alternative splicing‐dependent neurexin regulation are largely unknown. Here, we determined high‐resolution structures of the complex of neurexophilin‐1 and the second laminin/neurexin/sex‐hormone‐binding globulin domain (LNS2) of neurexin‐1 and examined how alternative splicing at splice site #2 (SS2) regulates the complex. Our data reveal a unique, extensive, neurexophilin–neurexin binding interface that extends the jelly‐roll β‐sandwich of LNS2 of neurexin‐1 into neurexophilin‐1. The SS2A insert of LNS2 augments this interface, increasing the binding affinity of LNS2 for neurexophilin‐1. Taken together, our data reveal an unexpected architecture of neurexophilin–neurexin complexes that accounts for the modulation of binding by alternative splicing, which in turn regulates the competition of neurexophilin for neurexin binding with other ligands.

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Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins

Cited by 32 publications

References 0 publications

Secretome analysis of nerve repair mediating Schwann cells reveals Smad‐dependent trophism

Secretome analysis of nerve repair mediating Schwann cells reveals Smad‐dependent trophism

Interplay between Anakonda, Gliotactin and M6 for tricellular junction assembly and anchoring of septate junctions inDrosophilaepithelium

Structures of neurexophilin–neurexin complexes reveal a regulatory mechanism of alternative splicing

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