5V2Q

CaV beta2a subunit: CaV1.2 AID-CEN complex

Summary for 5V2Q

• Entry DOI: 10.2210/pdb5v2q/pdb
• Related: 5V2P
• Descriptor: Voltage-dependent L-type calcium channel subunit beta-2,Voltage-dependent L-type calcium channel subunit beta-2, Voltage-dependent L-type calcium channel subunit alpha-1C, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: ion channel, signaling, calcium, transport protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 41540.35

Authors

Findeisen, F.,Campiglio, M.,Jo, H.,Rumpf, C.H.,Pope, L.,Flucher, B.,Degrado, W.F.,Minor, D.L. (deposition date: 2017-03-06, release date: 2017-07-19, Last modification date: 2023-10-04)

Primary citation

Findeisen, F.,Campiglio, M.,Jo, H.,Abderemane-Ali, F.,Rumpf, C.H.,Pope, L.,Rossen, N.D.,Flucher, B.E.,DeGrado, W.F.,Minor, D.L.
Stapled Voltage-Gated Calcium Channel (CaV) alpha-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.
ACS Chem Neurosci, 8:1313-1326, 2017

PubMed 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 (Ca) pore-forming subunit α-interaction domain (AID) and cytoplasmic β-subunit (Caβ). 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:Caβ interactions and reduce the entropic penalty associated with AID binding to Caβ. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the Caα:Caβ interaction that modulate Ca function in an Caβ 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 Ca modulator design.

PubMed: 28278376
DOI: 10.1021/acschemneuro.6b00454

Experimental method

X-RAY DIFFRACTION (1.7 Å)