Structural Research of G Protein-coupled Receptors (GPCRs) Class B2

G Protein-coupled Receptors (GPCRs) are a superfamily of cell membrane receptors that play a crucial role in cellular signaling and response to various extracellular stimuli. Among the different classes of GPCRs, class B2, also known as the adhesion GPCR family, stands as one of the least understood groups. The adhesion GPCR family exhibits a distinctive molecular structure that distinguishes them from other GPCR classes. GPCRs class B2 possess an extended N-terminal portion comprising diverse adhesion domains. Furthermore, they contain a well-conserved GPCR autoproteolysis-inducing (GAIN) domain immediately preceding the first transmembrane helix.

A defining characteristic of the aGPCR family is their autoproteolytic cleavage at a highly conserved GPCR proteolysis site (GPS) located within the GAIN domain. This intriguing feature has been proposed to be critical for the maturation and proper functioning of these receptors. Upon cleavage, the receptors generate two noncovalently associated fragments: an N-terminal fragment (NTF) consisting mostly of the extracellular domain, and a C-terminal fragment (CTF) containing a portion of the proteolysed GAIN domain and the transmembrane domain (TMD).

Recent studies further present research findings on two specific aGPCRs, ADGRD1 and ADGRF1. The study reveals that the stalk region preceding the first transmembrane helix acts as the tethered agonist by interacting extensively with the transmembrane domain. This stalk-transmembrane domain interaction pattern is shared among members of the aGPCR family. Interestingly, the study also indicates a cleavage-independent manner of receptor activation, supported by the structure of autoproteolysis-deficient ADGRF1. The activation process involves a cascade of inter-helix interaction cores, which are conserved in position but show sequence variability in ADGRD1 and ADGRF1. Additionally, the intracellular region of ADGRF1 contains a specific lipid-binding site, which is functionally significant and may be involved in recognizing the endogenous ADGRF1 ligand synaptamide.

Figure 1. Overall structures of G protein-bound ADGRD1 and ADGRF1. (Qi X, et al., 2022)

Table 1. Structural research of class B2 GPCRs.

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References

1. Qu X, et al. Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1. Nature. 2022, 604(7907): 779-785.
2. Zhu X, et al. Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling. Nature Communications. 2022, 13(1): 5513.