5v2p

Publication Abstract from PubMed

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 alpha-interaction domain (AID) and cytoplasmic beta-subunit (CaVbeta). 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:CaVbeta interactions and reduce the entropic penalty associated with AID binding to CaVbeta. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the CaValpha1:CaVbeta interaction that modulate CaV function in an CaVbeta 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.

Stapled Voltage-Gated Calcium Channel (CaV) alpha-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.,Findeisen F, Campiglio M, Jo H, Abderemane-Ali F, Rumpf CH, Pope L, Rossen ND, Flucher BE, DeGrado WF, Minor DL Jr ACS Chem Neurosci. 2017 Jun 21;8(6):1313-1326. doi: 10.1021/acschemneuro.6b00454., Epub 2017 Mar 17. PMID:28278376^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.