8ITL

Cryo-EM structure of GIPR splice variant 1 (SV1) in complex with Gs protein

Summary for 8ITL

• Entry DOI: 10.2210/pdb8itl/pdb
• EMDB information: 35706
• Descriptor: Gastric inhibitory polypeptide receptor, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• Functional Keywords: cryo-electron microscopy; g protein-coupled receptor;splice variant; receptor activation., structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 149953.25

Authors

Zhao, F.H.,Hang, K.N.,Zhou, Q.T.,Shao, L.J.,Li, H.,Li, W.Z.,Lin, S.,Dai, A.T.,Cai, X.Q.,Liu, Y.Y.,Xu, Y.N.,Feng, W.B.,Yang, D.H.,Wang, M.W. (deposition date: 2023-03-22, release date: 2023-10-18, Last modification date: 2024-11-13)

Primary citation

Zhao, F.,Hang, K.,Zhou, Q.,Shao, L.,Li, H.,Li, W.,Lin, S.,Dai, A.,Cai, X.,Liu, Y.,Xu, Y.,Feng, W.,Yang, D.,Wang, M.W.
Molecular basis of signal transduction mediated by the human GIPR splice variants.
Proc.Natl.Acad.Sci.USA, 120:e2306145120-e2306145120, 2023

PubMed Abstract: Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor).

PubMed: 37792509
DOI: 10.1073/pnas.2306145120

Experimental method

ELECTRON MICROSCOPY (3.23 Å)