Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling
Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and rel...
Saved in:
Published in | Nature communications Vol. 13; no. 1; p. 5513 |
---|---|
Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
20.09.2022
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate the transmembrane side of receptor. However, the detailed mechanism of aGPCR activation remains elusive. Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex with G
q
, G
s
, G
i
, G
12
and G
13.
The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G
12
and GPCR/G
13
engagements. A comparison of G
q
, G
s
, G
i
, G
12
and G
13
engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (αH5) of Gα subunit that separates G
q
/G
s
engagements from G
i
/G
12
/G
13
engagements. This is also where G
q
/G
s
bind the receptor through both hydrophobic and polar interaction, while G
i
/G
12
/G
13
engage receptor mainly through hydrophobic interaction. We further provide physiological evidence of GPR110 activation via stalk peptide. Taken together, our study fills the missing information of GPCR/G-protein engagement and provides a framework for understanding aGPCR activation and GPR110 signaling.
aGPCRs play key roles in multiple physiological processes. Here the authors report cryo-EM structures of GPR110 in complexes with G
q
, G
s
, G
i
, G
12
and G
13
protein to reveal a detailed mechanism of aGPCR activation via the tethered stalk peptide and principles of G-protein coupling and selectivity on GPR110. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-022-33173-4 |