A conserved peptide-binding pocket in HyNaC/ASIC ion channels DOI Creative Commons
Audrey Ortega-Ramírez, Simone Albani,

Michèle Bachmann

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(41)

Published: Oct. 4, 2024

The only known peptide-gated ion channels—FaNaCs/WaNaCs and HyNaCs—belong to different clades of the DEG/ENaC family. FaNaCs are activated by short neuropeptide FMRFamide, HyNaCs Hydra RFamides, which not evolutionarily related FMRFamide. FMRFamide-binding site in was recently identified a cleft atop large extracellular domain. However, this is conserved HyNaCs. Here, we combined molecular modeling site-directed mutagenesis putative binding pocket for Hydra-RFamides domain heterotrimeric HyNaC2/3/5. This localizes one three subunit interfaces, indicating that trimeric channel binds single peptide ligand. We engineered an unnatural amino acid at entrance, allowed covalent tethering RFamide channel, thereby trapping open conformation. same region as acidic acid-sensing channels (ASICs), ligands. less acidic, both electrostatic hydrophobic interactions contribute binding. Collectively, our results reveal ligand-binding ASICs indicate independent evolution peptide-binding cavities two subgroups channels.

Language: Английский

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

et al.

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(4), P. 717 - 726

Published: Feb. 9, 2024

Rapid signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning channel domain. The degenerin/epithelial sodium (DEG/ENaC) superfamily diverse in terms of its gating stimuli, some DEG/ENaCs gated neuropeptides, others pH, mechanical force or enzymatic activity. mechanism which ligands bind to activate poorly understood. Here we dissected the structural basis for neuropeptide-gated activity DEG/ENaC, FMRFamide-gated 1 (FaNaC1) from annelid worm Malacoceros fuliginosus, using cryo-electron microscopy. Structures FaNaC1 ligand-free resting state several ligand-bound states reveal site capture ligand-induced conformational changes gating, verified complementary mutagenesis experiments. Our results illuminate offer template experimental dissection pharmacology conduction.

Language: Английский

Citations

6
A conserved peptide-binding pocket in HyNaC/ASIC ion channels DOI Creative Commons
Audrey Ortega-Ramírez, Simone Albani,

Michèle Bachmann

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(41)

Published: Oct. 4, 2024

The only known peptide-gated ion channels—FaNaCs/WaNaCs and HyNaCs—belong to different clades of the DEG/ENaC family. FaNaCs are activated by short neuropeptide FMRFamide, HyNaCs Hydra RFamides, which not evolutionarily related FMRFamide. FMRFamide-binding site in was recently identified a cleft atop large extracellular domain. However, this is conserved HyNaCs. Here, we combined molecular modeling site-directed mutagenesis putative binding pocket for Hydra-RFamides domain heterotrimeric HyNaC2/3/5. This localizes one three subunit interfaces, indicating that trimeric channel binds single peptide ligand. We engineered an unnatural amino acid at entrance, allowed covalent tethering RFamide channel, thereby trapping open conformation. same region as acidic acid-sensing channels (ASICs), ligands. less acidic, both electrostatic hydrophobic interactions contribute binding. Collectively, our results reveal ligand-binding ASICs indicate independent evolution peptide-binding cavities two subgroups channels.

Language: Английский

Citations

2