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-Structure paper
| Title | The adhesion GPCR ADGRL2 engages Gα13 to enable epidermal differentiation. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 122, Issue 47, Page e2508436122, Year 2025 |
| Publish date | Nov 25, 2025 |
Authors | Xue Yang / Feng He / Vanessa Lopez-Pajares / Douglas F Porter / Krassimira Garbett / Zurab Siprashvili / Luca Ducoli / Robin M Meyers / David L Reynolds / Duy Lan Huong Bui / Audrey Hong / Duy Thanh Nguyen / Yuqing Jing / Smarajit Mondal / Lisa Ko / Shiying Tao / Bharti Singal / Richard Sando / Georgios Skiniotis / Paul A Khavari / ![]() |
| PubMed Abstract | 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 ...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 RNA-sequencing 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. Follow-up tissue knockouts verified that Gα13 is also required for epidermal differentiation. A cryoelectron microscopy structure in lipid nanodiscs showed that ADGRL2 engages with Gα13 at multiple interfaces, including via an interaction between ADGRL2 intracellular loop 3 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. |
External links | Proc Natl Acad Sci U S A / PubMed:41252157 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.9 Å |
| Structure data | EMDB-47522, PDB-9e51: |
| Chemicals | ![]() ChemComp-CLR: ![]() ChemComp-HOH: |
| Source |
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Keywords | SIGNALING PROTEIN / adhesion GPCR / Tethered agonist / Latrophilin-2 / LPHN2 (ADGRL2) / Heterotrimeric G protein / Cryo-EM / Lipid Nanodiscs / Membrane Protein |
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homo sapiens (human)
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