NPY6R

Model summary

A seven-helix membrane receptor that detects extracellular neuropeptide signals and converts them into intracellular inhibitory signaling. Its N-terminal and transmembrane architecture create a high-affinity binding pocket for neuropeptide hormones and an internal coupling interface that engages heterotrimeric G proteins. By stabilizing an active conformation at the cell surface, it suppresses adenylate cyclase activity and modulates downstream pathways that regulate neuronal and endocrine responses. The protein resides in the plasma membrane as a multi-pass receptor and likely signals through inhibitory G protein pathways with subsequent arrestin-mediated desensitization.

Predicted Gene Ontology terms

1. 01

   I begin with the InterPro architecture.

   The core transmembrane engine is IPR017452 (GPCR, rhodopsin-like, 7TM domain, residues 52–276), which establishes a seven-helix bundle that transduces extracellular ligand binding into intracellular G protein signaling. This rhodopsin-like scaffold is reinforced by IPR000276 (G protein-coupled receptor, rhodopsin-like family, residues 37–283), confirming a class A GPCR fold that couples to heterotrimeric G proteins. Multiple peptide-receptor–specific family signatures overlay this core: IPR000986 (Neuropeptide Y6 receptor family) appears in the extreme N-terminus (residues 2–20), then again at residues 21–36, and later at 171–185, 185–198, and 230–244. These repeated marks specify a receptor tuned for neuropeptide Y/peptide YY ligands and define the Y6 receptor subclass. Three additional family signatures—IPR000611 (Neuropeptide Y receptor family, residues 63–75, 93–105, 116–131)—sit within the N-terminal/TM-proximal region and further constrain the binding pocket and intracellular coupling surfaces typical of peptide-responsive class A GPCRs. The ordered layout—an N-terminal neuropeptide-recognition signature feeding into a canonical 7TM signaling core—causally dictates ligand capture outside the cell and G protein activation inside.

2. 02

   From this architecture, the molecular function resolves as follows.

   The rhodopsin-like 7TM bundle (IPR017452/IPR000276) confers G protein-coupled receptor activity that is specialized by neuropeptide receptor family markers (IPR000611, IPR000986) to neuropeptide hormone binding and receptor activity. This directly supports GO:0017046 peptide hormone binding and GO:0008188 neuropeptide receptor activity. The presence of multiple Y6-receptor–defining motifs indicates a binding cavity and intracellular interface optimized for inhibitory G protein coupling.

3. 03

   The biological process follows from this chemistry: ligand-triggered conformational changes in the 7TM core drive nucleotide exchange on heterotrimeric G proteins, initiating the GO:0007186 G protein-coupled receptor signaling pathway.

   In Y6-class receptors, this architecture typically biases toward Gi/o pathways, lowering cAMP and modulating ion channels and MAPK cascades.

4. 04

   Cellular location is dictated by the seven-helix bundle and extracellular ligand access: such receptors must reside in the plasma membrane to survey extracellular neuropeptides.

   This aligns with GO:0005886 plasma membrane and the experimentally consistent designation as a multi-pass cell-membrane protein.

5. 05

   Mechanistically, the N-terminal neuropeptide Y6-receptor signatures (residues 2–20, 21–36; 171–185, 185–198; 230–244) shape an extracellular binding surface that captures neuropeptide Y/peptide YY.

   Ligand engagement stabilizes an active 7TM conformation that recruits Gi/o, leading to βγ-mediated effector control and reduced adenylate cyclase activity. I therefore hypothesize interactions with Gi/o heterotrimers (GNAI/GNAO with Gβγ), β-arrestins for desensitization and endocytic routing, and GPCR kinases that tune signaling duration. Together, these features define a membrane-embedded neuropeptide sensor that transduces extracellular cues into intracellular inhibitory signaling.