RRC ID 75963
Author Gershkovich MM, Groß VE, Vu O, Schoeder CT, Meiler J, Prömel S, Kaiser A.
Title Structural Perspective on Ancient Neuropeptide Y-like System reveals Hallmark Features for Peptide Recognition and Receptor Activation.
Journal J Mol Biol
Abstract The neuropeptide Y (NPY) family is a peptide-activated G protein-coupled receptor system conserved across all bilaterians, and is involved in food intake, learning, and behavior. We hypothesized that comparing the NPY system in evolutionarily ancient organisms can reveal structural determinants of peptide recognition and receptor activation conserved in evolution. To test this hypothesis, we investigated the homologous FLP/NPR system of the protostome C.elegans. For three prototypic peptide-receptor complexes representing different ligand types, we integrate extensive functional data into structural models of the receptors. Common features include acidic patches in the extracellular loops (ECLs) of the receptors that cooperatively 'draw' the peptide into the binding pocket, which was functionally validated in vivo. A structurally conserved glutamate in the ECL2 anchors the peptides by a conserved salt bridge to the arginine of the RFamide motif. Beyond this conserved interaction, peptide binding show variability enabled by receptor-specific interactions. The family-conserved residue Q3.32 is a key player for peptide binding and receptor activation. Altered interaction patterns at Q3.32 may drastically increase the efficacy to activate the receptor.
Volume 433(13)
Pages 166992
Published 2021-6-25
DOI 10.1016/j.jmb.2021.166992
PII S0022-2836(21)00193-5
PMID 33865871
PMC PMC8380825
MeSH Amino Acid Motifs Amino Acid Sequence Animals Binding Sites Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / metabolism Humans Models, Molecular Mutation / genetics Neuropeptide Y / chemistry* Neuropeptide Y / metabolism* Protein Binding Receptors, Neuropeptide Y / chemistry Receptors, Neuropeptide Y / metabolism*
Resource
C.elegans