The Adhesion GPCR ADGRL2 engages Gα13 to Enable Epidermal Differentiation

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Detalles Bibliográficos
Publicado en:	bioRxiv (Feb 28, 2025)
Autor principal:	Yang, Xue
Otros Autores:	He, Feng, Porter, Douglas F, Garbett, Krassimira, Meyers, Robin M, Reynolds, David L, Lan Hung Bui Duy, Hong, Audrey, Ducoli, Luca, Siprashvili, Zurab, Lopez-Pajares, Vanessa, Mondal, Smarajit, Ko, Lisa, Jing, Yuqing, Tao, Shiying, Singal, Bharti, Sando, Richard, Skiniotis, Georgios, Khavari, Paul A
Publicado:	Cold Spring Harbor Laboratory Press
Materias:	Cell surface receptors Homeostasis CRISPR Mutation Microscopy Electron microscopy G protein-coupled receptors Glutamine Intracellular Epidermis Point mutation Interfaces Proteins Cell membranes
Acceso en línea:	Citation/Abstract Full Text - PDF Full text outside of ProQuest
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Descripción
Resumen:	Homeostasis relies on signaling networks controlled by cell membrane receptors. Although G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors, their specific roles in the epidermis are not fully understood. Dual CRISPR-Flow and single cell Perturb-seq knockout screens of all epidermal GPCRs were thus performed, uncovering an essential requirement for adhesion GPCR ADGRL2 (latrophilin 2) in epidermal differentiation. Among potential downstream guanine nucleotide-binding G proteins, ADGRL2 selectively activated Gα13. Perturb-seq of epidermal G proteins and follow-up tissue knockouts verified that Gα13 is also required for epidermal differentiation. A cryo-electron microscopy (cryo-EM) structure in lipid nanodiscs showed that ADGRL2 engages with Gα13 at multiple interfaces, including via a novel interaction between ADGRL2 intracellular loop 3 (ICL3) and a Gα13-specific QQQ glutamine triplet sequence in its GTPase domain. In situ gene mutation of this interface sequence impaired epidermal differentiation, highlighting an essential new role for an ADGRL2-Gα13 axis in epidermal differentiation.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Homeostasis relies on signaling networks controlled by cell membrane receptors. Although G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors, their specific roles in the epidermis are not fully understood. Dual CRISPR-Flow and single cell Perturb-seq knockout screens of all epidermal GPCRs were thus performed, uncovering an essential requirement for adhesion GPCR ADGRL2 (latrophilin 2) in epidermal differentiation. Among potential downstream guanine nucleotide-binding G proteins, ADGRL2 selectively activated Gα13. Perturb-seq of epidermal G proteins and follow-up tissue knockouts verified that Gα13 is also required for epidermal differentiation. A cryo-electron microscopy (cryo-EM) structure in lipid nanodiscs showed that ADGRL2 engages with Gα13 at multiple interfaces, including via a novel interaction between ADGRL2 intracellular loop 3 (ICL3) and a Gα13-specific QQQ glutamine triplet sequence in its GTPase domain. In situ gene mutation of this interface sequence impaired epidermal differentiation, highlighting an essential new role for an ADGRL2-Gα13 axis in epidermal differentiation.
ISSN:	2692-8205
DOI:	10.1101/2025.02.19.639154
Fuente:	Biological Science Database