9E51

Cryo-EM structure of human LPHN2 (ADGRL2)/G13 complex in lipid nanodiscs

Summary for 9E51

• Entry DOI: 10.2210/pdb9e51/pdb
• EMDB information: 47522
• Descriptor: Isoform 2 of Guanine nucleotide-binding protein subunit alpha-13, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: adhesion gpcr, tethered agonist, latrophilin-2, lphn2 (adgrl2), heterotrimeric g protein, cryo-em, lipid nanodiscs, membrane protein, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 109517.22

Authors

He, F.,Skiniotis, G. (deposition date: 2024-10-26, release date: 2025-11-12, Last modification date: 2026-03-04)

Primary citation

Yang, X.,He, F.,Lopez-Pajares, V.,Porter, D.F.,Garbett, K.,Siprashvili, Z.,Ducoli, L.,Meyers, R.M.,Reynolds, D.L.,Lan Huong Bui, D.,Hong, A.,Nguyen, D.T.,Jing, Y.,Mondal, S.,Ko, L.,Tao, S.,Singal, B.,Sando, R.,Skiniotis, G.,Khavari, P.A.
The adhesion GPCR ADGRL2 engages G alpha 13 to enable epidermal differentiation.
Proc.Natl.Acad.Sci.USA, 122:e2508436122-e2508436122, 2025

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 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.

PubMed: 41252157
DOI: 10.1073/pnas.2508436122

Experimental method

ELECTRON MICROSCOPY (2.9 Å)