The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms

Bui, Duy Lan Huong; Roach, Andrew T.; Li, Jingxian; Bandekar, Sumit J.; Orput, Elizabeth; Raghavan, Ritika; Araç, Demet; Sando, Richard

doi:10.1016/j.celrep.2023.112552

Cited by 9 publications

(7 citation statements)

References 64 publications

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“…Lphn3's function in synapse formation is known to require both its extracellular FLRT/teneurin-binding sequences and its intracellular regions, including its G protein-binding sequences 4,8 , but the molecular mechanisms by which Lphn3 induces synapse formation remain elusive. In cell-signaling assays multiple Ga proteins were reported to couple to Lphn3 9,10,11,12 and their binding was confirmed by cryo-EM structures 13,14 . However, it is unknown which Ga protein physiologically mediates Lphn3dependent synapse formation, it is unclear whether Ga protein signaling on its own constitutes the core mechanism of synapse formation, and it remains a puzzle how presynaptic ligand-binding to postsynaptic Lphn3 induces synapse formation.Here, we show that Lphn3 gene (Adgrl3) transcripts undergo extensive alternative splicing.The resulting protein variants couple to different Ga proteins.…”

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confidence: 90%

Activity-Dependent Alternative Splicing of Adhesion-GPCR Latrophilin-3 Controls Synapse Formation

Wang,

DeLeon,

Roth

et al. 2023

Preprint

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How synapses are assembled and specified in brain is incompletely understood. Latrophilin- 3, a postsynaptic adhesion-GPCR, mediates Schaffer-collateral synapse formation in the hippocampus but the mechanisms involved remained unclear. Here we show that Latrophilin-3 organizes synapses by a convergent dual-pathway mechanism by which Latrophilin-3 simultaneously activates GαS/cAMP-signaling and recruits phase-separated postsynaptic protein scaffolds. We found that cell type-specific alternative splicing of Latrophilin-3 controls its G protein coupling mode, resulting in Latrophilin-3 variants that predominantly signal via Gαsand cAMP or via Gα12/13. A CRISPR-mediated genetic switch of Latrophilin-3 alternative splicing from a GαS- to a Gα12/13-coupled mode impaired synaptic connectivity similar to the overall deletion of Latrophilin-3, suggesting that GαS/cAMP- signaling by Latrophilin-3 splice variants mediates synapse formation. Moreover, GαS- but not Gα12/13-coupled splice variants of Latrophilin-3 recruit phase-transitioned postsynaptic protein scaffolds that are clustered by binding of presynaptic Latrophilin-3 ligands. Strikingly, neuronal activity promotes alternative splicing of the synaptogenic variant of Latrophilin-3, thereby enhancing synaptic connectivity. Together, these data suggest that activity- dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways, GαS/cAMP signaling and the phase separation of postsynaptic protein scaffolds.

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confidence: 90%

Activity-Dependent Alternative Splicing of Adhesion-GPCR Latrophilin-3 Controls Synapse Formation

Wang,

DeLeon,

Roth

et al. 2023

Preprint

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“…mCELSR1 has previously been shown to couple to Gαs using a BRET2 assay for G protein coupling. 67 This assay measures the dissociation of Gα from Gβɣ which is caused by turnover of Gα into its GTPbound state by the 7TM (Figure 6A). This manifests as a decrease in BRET2.…”

Section: Celsr Signaling Activity Is Regulated By the Cadh9-gain Modulementioning

confidence: 99%

“…Our results show that the mCELSR1 CMM regulates G proteincoupling as its removal reduces Gαs turnover, and previous work has shown that this Gαs turnover is not affected by the mutation of residues on the tethered agonist which mediate activation in other aGPCRs. 67 Recent work which measured tethered agonist-mediated activation across all adhesion GPCRs shows that while some receptors clearly respond to the tethered agonist, CELSR1 and CELSR3 do not. 78 Taken together, this work suggests that in CELSR1, the CMM can modulate 7TM function independent of the canonical tethered agonist-mediated activation mechanism.…”

Section: An Updated View Of Adhesion Gpcr Structure and Function: The...mentioning

confidence: 99%

“…CELSR orthologs across different species variably include the residues for GAIN domain autoproteolysis. 66,67 No function has been demonstrated for this C-terminal EGF/LamG/HormR/GAIN region. The CELSR seven-transmembrane (7TM) region is thought to couple to Gαs and finally, CELSRs have a long intracellular region of about 300 residues.…”

Section: Introductionmentioning

confidence: 99%

“…The CELSR seven-transmembrane (7TM) region is thought to couple to Gαs and finally, CELSRs have a long intracellular region of about 300 residues. 67 Despite various hints of CELSR structure and function available in the literature, detailed information at the molecular level about these proteins is minimally present. In addition, mechanistic insight for how CELSRs convert adhesion into signaling remains unavailable.…”

Section: Introductionmentioning

confidence: 99%

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Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling

Bandekar,

Garbett,

Kordon

et al. 2024

Preprint

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Cadherin EGF Laminin G seven-pass G-type receptors (CELSRs) are conserved adhesion G protein-coupled receptors; CELSRs are essential for animal development. CELSRs have extracellular regions (ECRs) containing 23 adhesion domains which couple adhesion to intracellular signaling. However, molecular-level insight into CELSR function is sparsely available. We report the 4.3 Angstrom cryo-EM reconstruction of the mCELSR1 ECR with 13 domains resolved in the structure. These domains form a compact module mediated by interdomain interactions with contact between the N- and C-terminal domains. We show the mCELSR1 ECR forms an extended species in the presence of Ca2+, which we propose represents the antiparallel cadherin repeat dimer. Using assays for adhesion and G protein-coupling, we assign the N-terminal CADH1-8 module as necessary for cell adhesion and we show the C-terminal CAHD9-GAIN module regulates signaling. Our work provides important molecular context to the literature on CELSR function and opens the door towards further mechanistic studies.

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Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors

Dates,

Jones,

Smith

et al. 2024

Cell Chemical Biology

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The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms

Cited by 9 publications

References 64 publications

Activity-Dependent Alternative Splicing of Adhesion-GPCR Latrophilin-3 Controls Synapse Formation

Activity-Dependent Alternative Splicing of Adhesion-GPCR Latrophilin-3 Controls Synapse Formation

Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling

Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors

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