Adhesion G Protein-coupled Receptors

Chris de Graaf, Saskia Nijmeijer, Steffen Wolf, Oliver P. Ernst, Nijmeijer, Saskia, Wolf, Steffen, Ernst, Oliver P., Graaf, Chris

Tobias Langenhan, Torsten Schöneberg

Schematic presentation of the overall adhesion G Protein-Coupled Receptor (aGPCR) structure and functional domains, covering an extracellular N-terminal fragment (NTF), a membrane-spanning C-terminal fragment (CTF) and a GPCR proteolysis site (GPS). (Left side) aGPCR model constructed based on the seven-transmembrane (7TM) structure (blue) of secretin family glucagon receptor (GCGR) (PDB, 4L6R) [11] and the GPCR autoproteolysis inducing (GAIN) domain (magenta) structure of latrophilin 1 (PDB, 4DLQ) [9]. The β-13 strand residues are depicted in green. (Right side) The experimentally validated full-length secretin family GCGR structure combining structural and experimental information from the GCGR 7TM crystal structure (PDB, 4L6R) (blue), the GCGR extracellular domain (ECD) structure (PDB, 4ERS) (magenta) and the ECD structure of glucagon-like peptide-1 (GLP-1)-bound glucagon-like peptide-1 receptor (GLP-1R) (PDB, 3IOL) (green), complemented by site-directed mutagenesis, electron microscopy (EM), hydrogen-deuterium exchange (HDX) and cross-linking studies [11-13]) Despite the recent breakthroughs in the elucidation of the three-dimensional structures of the seven transmembrane (7TM) domain of the G protein-coupled receptor (GPCR) superfamily, a corresponding structure of a member of the adhesion GPCR (aGPCR) family has not yet been solved. In this chapter, we give an overview of the current knowledge of the 7TM domain of aGPCRs by comparative structure-based sequence similarity analyses between aGPCRs and GPCRs with known crystal structure. Of the GPCR superfamily, only the secretin family shares some sequence similarity with aGPCRs. This chapter will therefore emphasize on the comparison of these two GPCR families. Two 7TM domain structures of secretin family GPCRs are known that provide insight into the structure-function relationships of conserved sequence motifs that play important roles and are also present in most aGPCRs. This suggests that the 7TM domains of aGPCRs and secretin family GPCRs share a similar structural fold and that the conserved residues in both families may be involved in similar intermolecular interaction networks and facilitate similar conformational changes. Comparison of the residues that line the large peptide hormone binding pocket in the 7TM domain of secretin family GPCRs with corresponding residues in aGPCRs indicates that in the latter, the corresponding pocket in the 7TM domain is relatively hydrophobic and may be even larger. Improved knowledge on these conserved sequence motifs will help to understand the interactions of the aGPCR 7TM domain with ligands and gain insight into the activation mechanism of aGPCRs.