The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling DOI Open Access
Ethan Dintzner, Sumit J. Bandekar, Katherine Leon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 16, 2024

Abstract Adhesion G Protein–coupled receptors (aGPCRs) transduce extracellular adhesion signals into cytoplasmic signaling pathways. ADGRG6/GPR126 is an aGPCR critical for axon myelination, heart development and ear development; associated with developmental diseases cancers. ADGRG6 has a large, alternatively-spliced, five-domain region (ECR) that samples different conformations regulates receptor signaling. However, the molecular details of how ECR are unclear. Herein, we studied conformational dynamics conserved CUB domain which located at distal N-terminus deleted in alternatively-spliced isoform ( Δ CUB). We showed decreased Molecular simulations suggest involved interdomain contacts to maintain compact conformation. A cancer-associated mutant, C94Y, drastically perturbs conformation results elevated signaling, whereas another Y96A, near Ca 2+ -binding site, decreases Our ECR-mediated mechanism regulation instructs changes within regulate

Language: Английский

LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR DOI Creative Commons
Charles Bayly-Jones, Christopher J. Lupton, Alastair C. Keen

et al.

Nature, Journal Year: 2024, Volume and Issue: 634(8036), P. 1238 - 1244

Published: Oct. 2, 2024

Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense respond changes nutrient energy availability

Language: Английский

Citations

12
Size-reduced DREADD derivatives for AAV-assisted multimodal chemogenetic control of neuronal activity and behavior DOI Creative Commons
Takahito Miyake,

K. Tanaka,

Yoshiro Inoue

et al.

Cell Reports Methods, Journal Year: 2024, Volume and Issue: 4(10), P. 100881 - 100881

Published: Oct. 1, 2024

Language: Английский

Citations

4
Complex G-protein signaling of the adhesion GPCR, ADGRA3 DOI Creative Commons

Sven Bagger,

Hannes Schihada,

Anna L. Walser

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108441 - 108441

Published: March 1, 2025

Language: Английский

Citations

0
β-Arrestin Condensates Regulate G Protein-Coupled Receptor Function DOI Creative Commons
Preston J. Anderson, Peng Xiao, Ya-Ni Zhong

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

G protein-coupled receptors (GPCRs) are the largest class of in genome and control many signaling cascades essential for survival. GPCR is regulated by β-arrestins, multifunctional adapter proteins that direct receptor desensitization, internalization, signaling. While at GPCRs, β-arrestins interact with a wide array effectors, it unclear how promote such varied functions. Here we show undergo liquid-liquid phase separation (LLPS) to form condensates regulate function. We demonstrate β-arrestin oligomerization occurs proximity regulates functions as internalization This model supported cryoEM structure adhesion ADGRE1 2:2 complex 1, orientation can oligomerization. Our work provides paradigm regulators function, LLPS serving an important promoter compartmentalization GPCRs.

Language: Английский

Citations

0
Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function DOI Creative Commons
Szymon P. Kordon, Kristína Cechová, Sumit J. Bandekar

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 4, 2024

Adhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECRs) containing a conserved GAIN domain that precedes their seven-pass transmembrane (7TM). Ligand binding and mechanical force applied on the ECR regulate receptor function. However, how communicates with 7TM remains elusive, because relative orientation dynamics of within holoreceptor is unclear. Here, we describe cryo-EM reconstruction an aGPCR, Latrophilin3/ADGRL3, reveal adopts parallel to region has constrained movement. Single-molecule FRET experiments unveil three slow-exchanging states holoreceptor. GAIN-targeted antibodies, cancer-associated mutations at GAIN-7TM interface, alter states, conformations, signaling. Altogether, this data demonstrates conformational functional coupling between 7TM, suggesting ECR-mediated mechanism for aGPCR activation. GPCRs play role cellular communication. authors use single-molecule map changes domains offering new insights into

Language: Английский

Citations

1
Synaptic Gα12/13 signaling establishes hippocampal PV inhibitory circuits DOI Creative Commons
Krassimira Garbett,

Baris Tosun,

Jaybree M. Lopez

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(52)

Published: Dec. 18, 2024

Combinatorial networks of cell adhesion molecules and surface receptors drive fundamental aspects neural circuit establishment function. However, the intracellular signals orchestrated by these complexes remain less understood. Here, we report that Gα12/13 pathway lies downstream several GPCRs with critical synaptic functions. Impairment in postnatal hippocampal neurons diminishes inhibitory inputs without altering neuronal morphology or excitatory transmission. signaling CA1 vivo selectively regulates PV interneuron connectivity, supporting an synapse subtype-specific function this pathway. Our studies establish as a node shapes circuitry.

Language: Английский

Citations

1
The far extracellular CUB domain of the adhesion GPCR ADGRG6/GPR126 is a key regulator of receptor signaling DOI Open Access
Ethan Dintzner, Sumit J. Bandekar, Katherine Leon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 16, 2024

Abstract Adhesion G Protein–coupled receptors (aGPCRs) transduce extracellular adhesion signals into cytoplasmic signaling pathways. ADGRG6/GPR126 is an aGPCR critical for axon myelination, heart development and ear development; associated with developmental diseases cancers. ADGRG6 has a large, alternatively-spliced, five-domain region (ECR) that samples different conformations regulates receptor signaling. However, the molecular details of how ECR are unclear. Herein, we studied conformational dynamics conserved CUB domain which located at distal N-terminus deleted in alternatively-spliced isoform ( Δ CUB). We showed decreased Molecular simulations suggest involved interdomain contacts to maintain compact conformation. A cancer-associated mutant, C94Y, drastically perturbs conformation results elevated signaling, whereas another Y96A, near Ca 2+ -binding site, decreases Our ECR-mediated mechanism regulation instructs changes within regulate

Language: Английский

Citations

0