Stapled Voltage-Gated Calcium Channel (CaV) α-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function
| Autor: | Findeisen, Felix, Campiglio, Marta, Jo, Hyunil, Abderemane-Ali, Fayal, Rumpf, Christine H, Pope, Lianne, Rossen, Nathan D, Flucher, Bernhard E, DeGrado, William F, Minor, Daniel L |
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| Rok vydání: | 2017 |
| Předmět: |
Voltage-gated calcium channel
protein-protein interaction antagonist Voltage-gated calcium channel (CaV) 1.1 Normal biological development and functioning Ca-v beta interaction [AID] protein−protein interaction antagonist stapled peptide electrophysiology Protein Subunits Medicinal and Biomolecular Chemistry Underpinning research AID:CaVβ interaction CaVβ interaction [AID] Humans Protein Interaction Domains and Motifs Calcium Channels Peptides Research Article X-ray crystallography |
| Zdroj: | ACS chemical neuroscience, vol 8, iss 6 ACS Chemical Neuroscience |
| Popis: | For many voltage-gated ion channels (VGICs), creation of a properly functioning ion channel requires the formation of specific protein-protein interactions between the transmembrane pore-forming subunits and cystoplasmic accessory subunits. Despite the importance of such protein-protein interactions in VGIC function and assembly, their potential as sites for VGIC modulator development has been largely overlooked. Here, we develop meta-xylyl (m-xylyl) stapled peptides that target a prototypic VGIC high affinity protein-protein interaction, the interaction between the voltage-gated calcium channel (CaV) pore-forming subunit α-interaction domain (AID) and cytoplasmic β-subunit (CaVβ). We show using circular dichroism spectroscopy, X-ray crystallography, and isothermal titration calorimetry that the m-xylyl staples enhance AID helix formation are structurally compatible with native-like AID:CaVβ interactions and reduce the entropic penalty associated with AID binding to CaVβ. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the CaVα1:CaVβ interaction that modulate CaV function in an CaVβ isoform-selective manner. Together, our studies provide a proof-of-concept demonstration of the use of protein-protein interaction inhibitors to control VGIC function and point to strategies for improved AID-based CaV modulator design. |
| Databáze: | OpenAIRE |
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