Stapled Voltage-Gated Calcium Channel (Ca-v) alpha-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, Jr, Minor Daniel L |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Voltage-gated calcium channel
protein-protein interaction antagonist Protein Subunits Ca-v beta interaction [AID] CaVβ interaction [AID] Humans Protein Interaction Domains and Motifs protein−protein interaction antagonist Calcium Channels stapled peptide electrophysiology Peptides X-ray crystallography |
| Zdroj: | Findeisen, Felix; Campiglio, Marta; Jo, Hyunil; Abderemane-Ali, Fayal; Rumpf, Christine H; Pope, Lianne; et al.(2017). Stapled Voltage-Gated Calcium Channel (Ca-v) alpha-Interaction Domain (AID) Peptides Act As Selective Protein Protein Interaction Inhibitors of Cav Function. ACS CHEMICAL NEUROSCIENCE, 8(6), 1313-1326. doi: 10.1021/acschemneuro.6b00454. Lawrence Berkeley National Laboratory: Retrieved from: http://www.escholarship.org/uc/item/8r4345gb |
| DOI: | 10.1021/acschemneuro.6b00454. |
| 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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