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| Title | Constitutive signal bias mediated by the human GHRHR splice variant 1. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 118, Issue 40, Year 2021 |
| Publish date | Oct 5, 2021 |
 Authors | Zhaotong Cong / Fulai Zhou / Chao Zhang / Xinyu Zou / Huibing Zhang / Yuzhe Wang / Qingtong Zhou / Xiaoqing Cai / Qiaofeng Liu / Jie Li / Lijun Shao / Chunyou Mao / Xi Wang / Jihong Wu / Tian Xia / Li-Hua Zhao / Hualiang Jiang / Yan Zhang / H Eric Xu / Xi Cheng / Dehua Yang / Ming-Wei Wang /  |
| PubMed Abstract | Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing ...Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates G while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the state or GHRH-bound state in complex with the G protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, G versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation. |
 External links | Proc Natl Acad Sci U S A / PubMed:34599099 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.6 - 3.29 Å |
| Structure data | EMDB-31824, PDB-7v9l: EMDB-31825, PDB-7v9m: |
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 Keywords |  STRUCTURAL PROTEIN / class B GPCR / receptor bias / cancer / cell proliferation |
