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bioRxiv · 10.1101/2025.02.19.639154

The Adhesion GPCR ADGRL2 engages Gα13 to Enable Epidermal Differentiation

Yang, X.·He, F.·Porter, D. F.·Garbett, K.·Meyers, R. M.·Reynolds, D. L.·Duy, L. H. B.·Hong, A.·Ducoli, L.·Siprashvili, Z.·Lopez-Pajares, V.·Mondal, S.·Ko, L.·Jing, Y.·Tao, S.·Singal, B.·Sando, R.·Skiniotis, G.·Khavari, P. A.
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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 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 G13. Perturb-seq of epidermal G proteins and follow-up tissue knockouts verified that G13 is also required for epidermal differentiation. A cryo-electron microscopy (cryo-EM) structure in lipid nanodiscs showed that ADGRL2 engages with G13 at multiple interfaces, including via a novel interaction between ADGRL2 intracellular loop 3 (ICL3) and a G13-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-G13 axis in epidermal differentiation.

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Yang, X., He, F., Porter, D. F., Garbett, K., Meyers, R. M., Reynolds, D. L., Duy, L. H. B., Hong, A., Ducoli, L., Siprashvili, Z., Lopez-Pajares, V., Mondal, S., Ko, L., Jing, Y., Tao, S., Singal, B., Sando, R., Skiniotis, G., Khavari, P. A.. 2025-02-20. The Adhesion GPCR ADGRL2 engages Gα13 to Enable Epidermal Differentiation. https://doi.org/10.1101/2025.02.19.639154

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