Structural basis for excitatory neuropeptide signaling DOI Creative Commons
Valeria Kalienkova, Mowgli Dandamudi, Cristina Paulino

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 29, 2023

ABSTRACT Rapid chemo-electric signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning channel 1 . The degenerin/epithelial sodium (DEG/ENaC) superfamily, which occurs throughout the animal kingdom, unique in its diversity of gating stimuli, some DEG/ENaCs gated conventional ligands such as neuropeptides, others e.g. pH, mechanical force, or enzymatic activity 2-5 mechanism bind to activate poorly understood. We have therefore dissected structural basis for neuropeptide binding neuropeptide-gated DEG/ENaC, FMRFamide-gated (FaNaC1) from annelid worm Malacoceros fuliginosus 6 , using cryo-electron microscopy. High-resolution structures FaNaC1 ligand-free resting state several ligand-bound states reveal site capture ligand-induced conformational changes that mediate gating. Complementary mutagenesis experiments confirm functional roles particular amino acid residues implicated structures. Our results illuminate offer template experimental dissection pharmacology conduction characteristically metazoan superfamily.

Language: Английский

Structural basis for excitatory neuropeptide signaling DOI Creative Commons
Valeria Kalienkova, Mowgli Dandamudi, Cristina Paulino

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 29, 2023

ABSTRACT Rapid chemo-electric signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning channel 1 . The degenerin/epithelial sodium (DEG/ENaC) superfamily, which occurs throughout the animal kingdom, unique in its diversity of gating stimuli, some DEG/ENaCs gated conventional ligands such as neuropeptides, others e.g. pH, mechanical force, or enzymatic activity 2-5 mechanism bind to activate poorly understood. We have therefore dissected structural basis for neuropeptide binding neuropeptide-gated DEG/ENaC, FMRFamide-gated (FaNaC1) from annelid worm Malacoceros fuliginosus 6 , using cryo-electron microscopy. High-resolution structures FaNaC1 ligand-free resting state several ligand-bound states reveal site capture ligand-induced conformational changes that mediate gating. Complementary mutagenesis experiments confirm functional roles particular amino acid residues implicated structures. Our results illuminate offer template experimental dissection pharmacology conduction characteristically metazoan superfamily.

Language: Английский

Citations

0