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Stapled Voltage-Gated Calcium Channel (Ca-v) alpha-Interaction Domain (AID) Peptides Act As Selective Protein Protein Interaction Inhibitors of Cav Function

  • Author(s): 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
  • et al.
Abstract

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.

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