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

Florian Seufert; Yin Kwan Chung; Peter W Hildebrand; Tobias Langenhan

doi:10.1016/j.tibs.2023.05.007

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

Trends Biochem Sci. 2023 Aug;48(8):726-739. doi: 10.1016/j.tibs.2023.05.007. Epub 2023 Jun 21.

Authors

Florian Seufert¹, Yin Kwan Chung², Peter W Hildebrand³, Tobias Langenhan⁴

Affiliations

¹ Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstrasse 16-18, 04107 Leipzig, Germany.
² Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany.
³ Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstrasse 16-18, 04107 Leipzig, Germany; Institute of Medical Physics and Biophysics, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: peter.hildebrand@medizin.uni-leipzig.de.
⁴ Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany. Electronic address: tobias.langenhan@gmail.com.

PMID: 37349240
DOI: 10.1016/j.tibs.2023.05.007

Abstract

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.

Keywords: 7TM domain; G protein coupling; GAIN domain; adhesion GPCR (aGPCR); mechanobiology; tethered agonism.

Publication types

Review

MeSH terms

Cell Adhesion
Cell Membrane
Protein Interaction Domains and Motifs
Receptors, G-Protein-Coupled* / chemistry
Signal Transduction*
Structure-Activity Relationship

Substances

Receptors, G-Protein-Coupled