Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket
- Lilia Leisle*Lilia Leisle*Email: [email protected]Institute of Physiology, RWTH Aachen University, 52074 Aachen, GermanyMore by Lilia Leisle,
- Michael MargreiterMichael MargreiterComputational Biomedicine−Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, GermanyInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, GermanyMore by Michael Margreiter,
- Audrey Ortega-RamírezAudrey Ortega-RamírezInstitute of Physiology, RWTH Aachen University, 52074 Aachen, GermanyMore by Audrey Ortega-Ramírez,
- Elinor CleuversElinor CleuversInstitute of Physiology, RWTH Aachen University, 52074 Aachen, GermanyMore by Elinor Cleuvers,
- Michèle BachmannMichèle BachmannInstitute of Physiology, RWTH Aachen University, 52074 Aachen, GermanyMore by Michèle Bachmann,
- Giulia RossettiGiulia RossettiComputational Biomedicine−Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, GermanyJülich Supercomputing Center (JSC), Forschungszentrum Jülich, 52425 Jülich, GermanyDepartment of Neurology, RWTH Aachen University, 52074 Aachen, GermanyMore by Giulia Rossetti, and
- Stefan Gründer*Stefan Gründer*Email: [email protected]Institute of Physiology, RWTH Aachen University, 52074 Aachen, GermanyMore by Stefan Gründer
Abstract
Prolonged acidosis, as it occurs during ischemic stroke, induces neuronal death via acid-sensing ion channel 1a (ASIC1a). Concomitantly, it desensitizes ASIC1a, highlighting the pathophysiological significance of modulators of ASIC1a acid sensitivity. One such modulator is the opioid neuropeptide big dynorphin (Big Dyn) which binds to ASIC1a and enhances its activity during prolonged acidosis. The molecular determinants and dynamics of this interaction remain unclear, however. Here, we present a molecular interaction model showing a dynorphin peptide inserting deep into the acidic pocket of ASIC1a. We confirmed experimentally that the interaction is predominantly driven by electrostatic forces, and using noncanonical amino acids as photo-cross-linkers, we identified 16 residues in ASIC1a contributing to Big Dyn binding. Covalently tethering Big Dyn to its ASIC1a binding site dramatically decreased the proton sensitivity of channel activation, suggesting that Big Dyn stabilizes a resting conformation of ASIC1a and dissociates from its binding site during channel opening.
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