PXD048927

PXD048927 is an original dataset announced via ProteomeXchange.

Title	Structural and functional characterization of the IgSF21-Neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization
Description	The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and post-synaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. One such complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α regulates GABAergic synapse development in the mouse brain, but the precise molecular mechanisms underlying this activity remain unclear. Here, we reveal that the interaction between presynaptic Nrxn2α and postsynaptic IgSF21 is a high-affinity receptor-ligand interaction and identify a binding interface in the IgSF21-Nrxn2α complex. Despite being expressed in both dendritic and somatic regions, IgSF21 preferentially regulates dendritic GABAergic presynaptic differentiation whereas another canonical Nrxn ligand, neuroligin2 (Nlgn2), regulates primarily perisomatic presynaptic differentiation. To explore mechanisms that could underly this compartment specificity, we targeted multiple signaling pathways pharmacologically while monitoring the synaptogenic activity of IgSF21 and Nlgn2. Interestingly, both IgSF21 and Nlgn2 require c-jun N-terminal kinase (JNK)-mediated signaling, whereas Nlgn2, but not IgSF21, additionally requires CaMKII and Src kinase activity. JNK inhibition diminished de novo presynaptic differentiation without affecting the maintenance of formed synapses. We further found that Nrxn2α knockout brains exhibit altered synaptic JNK activity in a sex-specific fashion, suggesting functional linkage between Nrxns and JNK in vivo. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21 and Nlgn downstream of Nrxn2α. We therefore propose a revised hypothesis that Nrxns act as molecular hubs to specify synaptic properties not only through their multiple extracellular ligands but also through distinct intracellular signaling pathways of these ligands.
HostingRepository	PRIDE
AnnounceDate	2024-03-04
AnnouncementXML	Submission_2024-03-04_07:19:37.218.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD048927
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Christian Poitras
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-26 14:07:46	ID requested
⏵ 1	2024-03-04 07:19:37	announced

10.3389/FNMOL.2024.1371145;

10.6019/PXD048927;

submitter keyword: c-jun N-terminal kinase,GABAergic synapse, Src kinase, CaMKII kinase, Neurexin2α, Signal transduction, IgSF21, Neuroligin2

Hideto Takahashi
contact affiliation	Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, H2W 1R7, Canada Integrated Program in Neuroscience, McGill University, Montreal, Quebec, H3A 2B2, Canada Department of Medicine, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada Division of Experimental Medicine, McGill University, Montreal, Quebec, H3A 0G4, Canada
contact email	Hideto.Takahashi@ircm.qc.ca
lab head
Christian Poitras
contact affiliation	Laboratory of Gene Transcription and Proteomics Discovery Platform, Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada
contact email	christian.poitras@ircm.qc.ca
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/03/PXD048927

PRIDE project URI

• PRIDE
  1. PXD048927
     1. Label: PRIDE project
     2. Name: Structural and functional characterization of the IgSF21-Neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization