A conserved peptide-binding pocket in HyNaC/ASIC ion channels.

Autor:	Ortega-Ramírez AM; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Albani S; Computational Biomedicine-Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, Germany.; Jülich Supercomputing Center, Forschungszentrum Jülich, 52425 Jülich, Germany.; Department of Neurology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Bachmann M; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Schmidt A; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Pinoé-Schmidt M; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Assmann M; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Augustinowski K; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Rossetti G; Computational Biomedicine-Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, Germany.; Jülich Supercomputing Center, Forschungszentrum Jülich, 52425 Jülich, Germany.; Department of Neurology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany., Gründer S; Medical Faculty, Institute of Physiology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 08; Vol. 121 (41), pp. e2409097121. Date of Electronic Publication: 2024 Oct 04.
DOI:	10.1073/pnas.2409097121
Abstrakt:	The only known peptide-gated ion channels-FaNaCs/WaNaCs and HyNaCs-belong to different clades of the DEG/ENaC family. FaNaCs are activated by the short neuropeptide FMRFamide, and HyNaCs by Hydra RFamides, which are not evolutionarily related to FMRFamide. The FMRFamide-binding site in FaNaCs was recently identified in a cleft atop the large extracellular domain. However, this cleft is not conserved in HyNaCs. Here, we combined molecular modeling and site-directed mutagenesis and identified a putative binding pocket for Hydra-RFamides in the extracellular domain of the heterotrimeric HyNaC2/3/5. This pocket localizes to only one of the three subunit interfaces, indicating that this trimeric ion channel binds a single peptide ligand. We engineered an unnatural amino acid at the putative binding pocket entrance, which allowed covalent tethering of Hydra RFamide to the channel, thereby trapping the channel in an open conformation. The identified pocket localizes to the same region as the acidic pocket of acid-sensing ion channels (ASICs), which binds peptide ligands. The pocket in HyNaCs is less acidic, and both electrostatic and hydrophobic interactions contribute to peptide binding. Collectively, our results reveal a conserved ligand-binding pocket in HyNaCs and ASICs and indicate independent evolution of peptide-binding cavities in the two subgroups of peptide-gated ion channels. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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