The netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABAA receptors

Zhou, Xin J.; Gueydan, Marine; Jospin, Maëlle; Ji, Tingting; Valfort, Aurore; Pinan‐Lucarré, Bérangère; Bessereau, Jean-Louis

doi:10.1038/s41467-020-16473-5

Cited by 24 publications

(64 citation statements)

References 82 publications

(112 reference statements)

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“…Interestingly, the FERM domain alone was not able to rescue N-AChR clustering defects, as also observed for GABA receptors at inhibitory NMJs (Fig. 6A) (Zhou et al, 2020).…”

Section: Frm-3/farp Bridges A7-like N-achrs With Lin-2/cask and Sdn-1supporting

confidence: 59%

“…5A, B). We previously demonstrated that LIN-2, the ortholog of CASK that contains a PDZ domain, was present at GABAergic NMJs where it promotes the recruitment of GABA A Rs at GABAergic synapses (Zhou et al, 2020). Over the course of that study, we also showed that LIN-2/CASK was additionally present at cholinergic synapses.…”

Section: Resultsmentioning

confidence: 99%

“…Our data show that FRM-3 and LIN-2 are both critical for SDN-1 dependent clustering of N-AChR at cholinergic synapses. We and others previously identified physical interactions between FRM-3 and LIN-2 (Tong et al, 2015;Zhou et al, 2020). We therefore hypothesized that they might form a complex connecting N-AChR and SDN-1.…”

Section: Frm-3/farp Bridges A7-like N-achrs With Lin-2/cask and Sdn-1mentioning

confidence: 90%

“…Second, it binds, recruits, and likely activates the netrin receptor UNC-40/DCC, which controls the synaptic content of GABA A Rs (Tu et al, 2015). UNC-40/DCC nucleates an intracellular scaffold by physically interacting with FRM-3, a FERM (p4.1, Ezrin, Radixin, Moesin) protein orthologous to FARP1/2 (Zhou et al, 2020). FRM-3 multimerizes and recruits LIN-2, the ortholog of CASK (Calcium calmodulin dependent Serine/Threonine kinase), which might provide a hub to physically connect the GABA A Rs, FRM-3/FARP and NLG-1/neuroligin.…”

Section: Introductionmentioning

confidence: 99%

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The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans

Zhou

Vachon

Cizeron

et al. 2020

Preprint

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SUMMARYThe extracellular matrix has emerged as an active component of chemical synapses regulating synaptic formation, maintenance and homeostasis. The heparan sulfate proteoglycan syndecans are known to regulate cellular and axonal migration in the brain. They are also enriched at synapses, but their synaptic functions remain more elusive. Here we show that SDN-1, the sole ortholog of syndecan in C. elegans, is absolutely required for the synaptic clustering of homomeric α7-like N-acetylcholine receptors (AChR) and regulates the synaptic content of heteromeric L-AChRs. SDN-1 is concentrated at neuromuscular junctions (NMJs) by the neurally-secreted synaptic organizer Ce-Punctin/MADD-4, which also activates the transmembrane netrin receptor DCC. Those cooperatively recruit the FARP and CASK orthologues that localize N-AChRs at cholinergic NMJs through physical interactions. Therefore, SDN-1 stands at the core of the cholinergic synapse organization by bridging the extracellular synaptic determinants to the intracellular synaptic scaffold that controls the postsynaptic receptor content.

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“…Interestingly, the FERM domain alone was not able to rescue N-AChR clustering defects, as also observed for GABA receptors at inhibitory NMJs (Fig. 6A) (Zhou et al, 2020).…”

Section: Frm-3/farp Bridges A7-like N-achrs With Lin-2/cask and Sdn-1supporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Frm-3/farp Bridges A7-like N-achrs With Lin-2/cask and Sdn-1mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans

Zhou

Vachon

Cizeron

et al. 2020

Preprint

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“…Otherwise, the complex has not been identified in other cellular processes. LIN-2 and LIN-10 have been independently implicated in neuronal cell traffic (Rongo et al, 1998, Wu et al, 2016 and in muscle, LIN-2 localizes to neuromuscular junctions along the nerve cord (Tong et al, 2015, Zhou et al, 2020. Our findings of prominent expression of LIN-2/7/10 proteins in neuronal tissue, strong colocalization of LIN-2 and LIN-7 in the neural ring and nerve chords, and the role of the mammalian CASK/Lin7/APBA1 complex in regulating synaptic plasticity and function, suggests the complex may also form in C. elegans neurons.…”

mentioning

confidence: 99%

Dynamic expression and localization of the LIN-2/7/10 protein scaffolding complex duringC. elegansvulval development

Gauthier

Rocheleau

2020

Preprint

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The evolutionarily conserved LIN-2 (CASK)/LIN-7 (Lin7A-C)/LIN-10 (APBA1) complex plays an important role in regulating spatial organization of membrane proteins and signaling components. In C. elegans, the complex is essential for development of the vulva by promoting the localization of the sole Epidermal Growth Factor Receptor (EGFR) orthologue, LET-23, to the basolateral membrane of the vulva precursor cells (VPCs) where it can specify the vulval cell fate. However, the expression and localization of the LIN-2/7/10 complex, and how the complex regulates receptor localization, are not known. Here we describe an in vivo analysis of the complex in C. elegans VPCs. Only LIN-7 colocalizes with LET-23 EGFR at the basolateral membrane, while the LIN-2/7/10 complex components instead colocalize at cytoplasmic foci, consistent with Golgi or endosomes. LIN-10 recruits LIN-2, which in turn recruits LIN-7. We demonstrate that the complex forms in vivo with particularly strong interaction and colocalization between LIN-2 and LIN-7. Our data suggest that the LIN-2/7/10 complex forms on endomembrane compartments where it likely targets LET-23 EGFR to the basolateral membrane, and point to distinct regulation between LIN-2/7 and LIN-10.Summary StatementLIN-10 recruits LIN-2 and LIN-7 to Golgi or recycling endosomes, consistent with targeting rather than tethering the epidermal growth factor receptor to the basolateral membrane in C. elegans.

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Prediction of interactions between cell surface proteins by machine learning

Su,

Griffin,

Emmons

et al. 2023

Proteins

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Cells detect changes in their external environments or communicate with each other through proteins on their surfaces. These cell surface proteins form a complicated network of interactions in order to fulfill their functions. The interactions between cell surface proteins are highly dynamic and, thus, challenging to detect using traditional experimental techniques. Here, we tackle this challenge using a computational framework. The primary focus of the framework is to develop new tools to identify interactions between domains in the immunoglobulin (Ig) fold, which is the most abundant domain family in cell surface proteins. These interactions could be formed between ligands and receptors from different cells or between proteins on the same cell surface. In practice, we collected all structural data on Ig domain interactions and transformed them into an interface fragment pair library. A high‐dimensional profile can then be constructed from the library for a given pair of query protein sequences. Multiple machine learning models were used to read this profile so that the probability of interaction between the query proteins could be predicted. We tested our models on an experimentally derived dataset that contains 564 cell surface proteins in humans. The cross‐validation results show that we can achieve higher than 70% accuracy in identifying the PPIs within this dataset. We then applied this method to a group of 46 cell surface proteins in Caenorhabditis elegans. We screened every possible interaction between these proteins. Many interactions recognized by our machine learning classifiers have been experimentally confirmed in the literature. In conclusion, our computational platform serves as a useful tool to help identify potential new interactions between cell surface proteins in addition to current state‐of‐the‐art experimental techniques. The tool is freely accessible for use by the scientific community. Moreover, the general framework of the machine learning classification can also be extended to study the interactions of proteins in other domain superfamilies.

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The netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABAA receptors

Cited by 24 publications

References 82 publications

The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans

The HSPG Syndecan is a core organizer of cholinergic synapses inC. elegans

Dynamic expression and localization of the LIN-2/7/10 protein scaffolding complex duringC. elegansvulval development

Prediction of interactions between cell surface proteins by machine learning

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