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Stapled Voltage-Gated Calcium Channel (CaV) ?-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.

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 ?-interaction domain (AID) and cytoplasmic ?-subunit (CaV?). 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:CaV? interactions and reduce the entropic penalty associated with AID binding to CaV?. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the CaV?1:CaV? interaction that modulate CaV function in an CaV? 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.

SUBMITTER: Findeisen F

PROVIDER: S-EPMC5481814 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Stapled Voltage-Gated Calcium Channel (Ca<sub>V</sub>) α-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of Ca<sub>V</sub> Function.

Findeisen Felix F Campiglio Marta M Jo Hyunil H Abderemane-Ali Fayal F Rumpf Christine H CH Pope Lianne L Rossen Nathan D ND Flucher Bernhard E BE DeGrado William F WF Minor Daniel L DL

ACS chemical neuroscience 20170317 6

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 VGI ...[more]

PMID: 28278376

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Project description:BackgroundFlavonoids in Chinese Medicine have been proven in animal studies that could aid in osteogenesis and bone formation. However, there is no consented mechanism for how these phytochemicals action on the bone-forming osteoblasts, and henceforth the prediction model of chemical screening for this specific biochemical function has not been established. The purpose of this study was to develop a novel selection and effective approach of flavonoids on the prediction of bone-forming ability via osteoblastic voltage-gated calcium (CaV) activation and inhibition using molecular modelling technique.MethodQuantitative structure-activity relationship (QSAR) in supervised maching-learning approach is applied in this study to predict the behavioral manifestations of flavonoids in the CaV channels, and developing statistical correlation between the biochemical features and the behavioral manifestations of 24 compounds (Training set: Kaempferol, Taxifolin, Daidzein, Morin, Scutellarein, Quercetin, Apigenin, Myricetin, Tamarixetin, Rutin, Genistein, 5,7,2'-Trihydroxyflavone, Baicalein, Luteolin, Galangin, Chrysin, Isorhamnetin, Naringin, 3-Methyl galangin, Resokaempferol; test set: 5-Hydroxyflavone, 3,6,4'-Trihydroxyflavone, 3,4'-Dihydroxyflavone and Naringenin). Based on statistical algorithm, QSAR provides a reasonable basis for establishing a predictive correlation model by a variety of molecular descriptors that are able to identify as well as analyse the biochemical features of flavonoids that engaged in activating or inhibiting the CaV channels for osteoblasts.ResultsThe model has shown these flavonoids have high activating effects on CaV channel for osteogenesis. In addition, scutellarein was ranked the highest among the screened flavonoids, and other lower ranked compounds, such as daidzein, quercetin, genistein and naringin, have shown the same descending order as previous animal studies.ConclusionThis predictive modelling study has confirmed and validated the biochemical activity of the flavonoids in the osteoblastic CaV activation.

Dataset Information

Stapled Voltage-Gated Calcium Channel (CaV) ?-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.

Publications

Stapled Voltage-Gated Calcium Channel (Ca<sub>V</sub>) α-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of Ca<sub>V</sub> Function.

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