ArticleStructure (London, England : 1993)2008
Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaValpha1 AID-CaVbeta interaction site that is critical for channel modulation.
Article in Structure (London, England : 1993), 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
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- Novel Peptide Therapeutics Targeting the L-Type Calcium Channel Prevent Hypertrophic Cardiomyopathy by Decreasing Mitochondrial Energetics.JACC. Basic to translational science · 2025Article
- Casein Kinase 2 Regulates the Intrinsic Activity of L-Type Calcium Currents in Cardiomyocytes.International journal of molecular sciences · 2025Article
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- Mapping the interaction surface between CaNature communications · 2025Article
- Electrosome assembly: Structural insights from high voltage-activated calcium channel (CaV)-chaperone interactions.Biochemical Society transactions · 2025Review
- Extracellular vesicles for developing targeted hearing loss therapy.Journal of controlled release : official journal of the Controlled Release Society · 2024Review
- EMC chaperone-CaNature · 2023Article
- β subunits of voltage-gated calcium channels in cardiovascular diseases.Frontiers in cardiovascular medicine · 2023Review
- Selective posttranslational inhibition of CaNature communications · 2022Article
- Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.Molecules (Basel, Switzerland) · 2022Review
- Adrenergic Regulation of Calcium Channels in the Heart.Annual review of physiology · 2022Review
- Co-Silencing of the Voltage-Gated Calcium Channel β Subunit and High-Voltage Activated αInternational journal of molecular sciences · 2022Article
- Mechanisms and Regulation of Cardiac CaInternational journal of molecular sciences · 2021Review
- Adrenergic CaCirculation research · 2021Article
- Disruption of the Key CaCell reports · 2019Article
- Article
- Development and Optimization of Expression, Purification, and ATPase Assay of KaiC for Medium-Throughput Screening of Circadian Clock Mutants in Cyanobacteria.International journal of molecular sciences · 2019Article
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Authors and funding
5 authors.
Funding
Abstract
Voltage-gated calcium channels (CaVs) are large, multisubunit complexes that control cellular calcium entry. CaV pore-forming (CaValpha1) and cytoplasmic (CaVbeta) subunits associate through a high-affinity interaction between the CaValpha1 alpha interaction domain (AID) and CaVbeta alpha binding pocket (ABP). Here we analyze AID-ABP interaction thermodynamics using isothermal titration calorimetry. We find that commensurate with their strong sequence similarity, all CaV1 and CaV2 AID peptides bind CaVbeta with similar nanomolar affinities. Although the AID-ABP interface encompasses 24 side chains, alanine-scanning mutagenesis reveals that the binding energy is focused in two complementary hotspots comprising four deeply conserved residues. Electrophysiological experiments show that hotspot interaction disruption prevents trafficking and functional modulation of CaV1.2 by CaVbeta. Together, the data support the primacy of the AID-ABP interface for CaValpha1-CaVbeta association, underscore the idea that hotspots dominate protein-protein interaction affinities, and uncover a target for strategies to control cellular excitability by blocking CaValpha1-CaVbeta complex formation.
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Registered trials
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