7TM domain structures of adhesion GPCRs: what's new and what's missing?

Heptahelical transmembrane (7TM) domains of adhesion-type G protein-coupled receptors (aGPCRs) have proved to be recalcitrant to structural biological interrogation for a long time and their unusual mode of activation has underlined their peculiarity within the superfamily of GPCRs. Nearly 30 structures of 7TM domains of human and mouse aGPCRs have now been released within a short period of time that cover a quarter of all mammalian aGPCRs and support the fundamental principles of aGPCR signaling. Nonetheless, several key questions on adhesion GPCR activation, signaling, and physiology remain open. Adhesion-type G protein-coupled receptors (aGPCRs) have long resisted approaches to resolve the structural details of their heptahelical transmembrane (7TM) domains. Single-particle cryogenic electron microscopy (cryo-EM) has recently produced aGPCR 7TM domain structures for ADGRD1, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRF1, and ADGRL3. We review the unique properties, including the position and conformation of their activating tethered agonist (TA) and signaling motifs within the 7TM bundle, that the novel structures have helped to identify. We also discuss questions that the kaleidoscope of novel aGPCR 7TM domain structures have left unanswered. These concern the relative positions, orientations, and interactions of the 7TM and GPCR autoproteolysis-inducing (GAIN) domains with one another. Clarifying their interplay remains an important goal of future structural studies on aGPCRs. Adhesion-type G protein-coupled receptors (aGPCRs) have long resisted approaches to resolve the structural details of their heptahelical transmembrane (7TM) domains. Single-particle cryogenic electron microscopy (cryo-EM) has recently produced aGPCR 7TM domain structures for ADGRD1, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRF1, and ADGRL3. We review the unique properties, including the position and conformation of their activating tethered agonist (TA) and signaling motifs within the 7TM bundle, that the novel structures have helped to identify. We also discuss questions that the kaleidoscope of novel aGPCR 7TM domain structures have left unanswered. These concern the relative positions, orientations, and interactions of the 7TM and GPCR autoproteolysis-inducing (GAIN) domains with one another. Clarifying their interplay remains an important goal of future structural studies on aGPCRs. also known as family B2 GPCRs, these constitute one of the five main branches of the GPCR superfamily. They contain GAIN–7TM domain pairs, and many aGPCRs additionally harbor elaborate extracellular adhesive domains for interactions with matricellular and membrane-linked ligands. posits that the NTF–CTF heterodimer is physically separated to initiate and sustain receptor activity. an extracellular hallmark domain of all aGPCRs (except ADGRA1) that is positioned immediately adjacent to the 7TM domain. Most aGPCRs are self-cleaved within the GAIN domain at a GPCR proteolysis site (GPS) which generates N- and C-terminal receptor fragments (NTF and CTF, respectively). The GAIN domain therefore contributes to both the NTF and the CTF. The NTF and the CTF remain non-covalently bound to one another after cleavage. the hallmark domain of all GPCRs. Structural changes in the 7TM domain upon ligand binding or stimulus encounter pass the extracellular signal across the membrane to intracellular messengers such as G proteins. molecules that perceive and transduce force stimuli into intracellular responses. Can be located in membrane systems (e.g., aGPCRs and ion channels) or intracellularly (e.g., cytoskeletal components). suggests that the NTF and the CTF cooperate during receptor activation without physical disruption of the NTF–CTF heterodimer. the most C-terminal β-strand of the intact GAIN domain that is positioned C-terminal to the GPS. It remains connected to the CTF after receptor cleavage, and is necessary and sufficient for aGPCR activation. uses the X.YY format to denote the transmembrane helix number (X) and residue position (YY) relative to the most conserved residue in the helix (e.g., X.50). The numbering is used to refer to structurally equivalent residue positions in different class B GPCRs.