Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function

Lee, Hubert; Chofflet, Nicolas; Liu, Jianfang; Fan, Shanghua; Lu, Zhuoyang; Rojas, MartinResua; Penndorf, Patrick; Bailey, Aaron O.; Russell, William K.; Machius, Mischa; Ren, Gang; Takahashi, Hideto; Rudenko, Gabby

doi:10.1016/j.jbc.2023.104586

Cited by 3 publications

(4 citation statements)

References 67 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, our previous study showed that deletion of the IgSF21 Ig3 domain significantly decreases, but does not fully disrupt, the binding of IgSF21 to Nrxn2α ( Tanabe et al, 2017 ). Furthermore, we recently found that the three-dimensional conformation and orientation of synaptic organizers, as presented as full-length proteins within the confines of the synaptic cleft, is a critical determinant of synapse organizer complex formation ( Lee H. et al, 2023 ). Therefore, it will be important to resolve the interaction between full length IgSF21 and Nrxn2α in future structural studies.…”

Section: Discussionmentioning

confidence: 99%

“…Cocultures of hippocampal neurons with HEK293T cells were set up as previously described ( Tanabe et al, 2017 ; Lee H. et al, 2023 ). For neuron-HEK293T coculture assays, appropriate extracellularly HA-tagged plasmids were transfected in HEK293T cells using TransIT-LT1 (Mirus Bio.…”

Section: Methodsmentioning

confidence: 99%

“…Purified human IgSF21-His (R&D Systems; #10330-S2) was purchased from R&D Systems. Protein binding assays were performed as described previously ( Tanabe et al, 2017 ; Lee H. et al, 2023 ). Briefly, to assess protein binding on the surface of COS7 cells, the cells were transfected using TransIT-LT1 (Mirus Bio.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization

Chofflet,

Naito,

Pastore

et al. 2024

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and postsynaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. Here, we focus on a synapse organizing complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α (Nrxn2α) that regulates GABAergic synapse development in the mouse brain. 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), primarily regulates perisomatic presynaptic differentiation. To explore mechanisms that could underlie 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. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21-Nrxn2α and Nlgn2-Nrxn synaptic organizing complexes in vitro. 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization

Chofflet,

Naito,

Pastore

et al. 2024

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, Lee et al. ( 7 ) conducted a study to investigate the structure–function relationships of MDGAs by combining a series of biophysical and structural techniques with cell-based assays. Previous studies had revealed that the surface on neuroligins where MDGA1 binds overlaps with the site where neurexins bind, indicating that MDGAs sterically block neurexins from binding to neuroligins ( 4 , 5 ).…”

mentioning

confidence: 99%

Organizing the synaptic junctions

Zhou¹

2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

An extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano

Sonani,

Palmer,

Esteves

et al. 2024

Nat Commun

View full text Add to dashboard Cite

A contractile sheath and rigid tube assembly is a widespread apparatus used by bacteriophages, tailocins, and the bacterial type VI secretion system to penetrate cell membranes. In this mechanism, contraction of an external sheath powers the motion of an inner tube through the membrane. The structure, energetics, and mechanism of the machinery imply rigidity and straightness. The contractile tail of Agrobacterium tumefaciens bacteriophage Milano is flexible and bent to varying degrees, which sets it apart from other contractile tail-like systems. Here, we report structures of the Milano tail including the sheath-tube complex, baseplate, and putative receptor-binding proteins. The flexible-to-rigid transformation of the Milano tail upon contraction can be explained by unique electrostatic properties of the tail tube and sheath. All components of the Milano tail, including sheath subunits, are crosslinked by disulfides, some of which must be reduced for contraction to occur. The putative receptor-binding complex of Milano contains a tailspike, a tail fiber, and at least two small proteins that form a garland around the distal ends of the tailspikes and tail fibers. Despite being flagellotropic, Milano lacks thread-like tail filaments that can wrap around the flagellum, and is thus likely to employ a different binding mechanism.

show abstract

Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function

Cited by 3 publications

References 67 publications

Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization

Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization

Organizing the synaptic junctions

An extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano

Contact Info

Product

Resources

About