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Related Concept Videos

Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

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Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
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Pull-down of Calmodulin-binding Proteins
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Dynamic-Structure Redesign of Calmodulin Reveals Mechanistic Constraints on Ryr2 Regulation.

Vladimir Bogdanov1,2, Svetlana Tikunova1,2, Nicolas Fadell2

  • 1The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, 43210.

Biorxiv : the Preprint Server for Biology
|April 27, 2026
PubMed
Summary
This summary is machine-generated.

Computational protein design can reengineer calmodulin (CaM), a key calcium sensor. Incorporating dynamic structures, not just static ones, is crucial for functional CaM redesign and treating diseases linked to calcium signaling.

Keywords:
Biological SciencesBiophysics and Computational BiologyMajorMinorcalcium signalingcalmodulincardiac physiologymolecular dynamics simulationsprotein engineeringryanodine receptor

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • Calmodulin (CaM) is a vital calcium (Ca2+) sensor regulating numerous cellular processes.
  • CaM's evolutionary conservation and flexibility make it challenging to redesign rationally.
  • Understanding CaM's role in Ca2+ signaling is critical for disease intervention.

Purpose of the Study:

  • To investigate if incorporating conformational dynamics into computational protein design can enable functional reengineering of CaM.
  • To test a dynamic-structure redesign strategy for CaM using the Ryanodine receptor 2 (RyR2) as a model.
  • To determine if enhanced binding affinity alone is sufficient for improved CaM function.

Main Methods:

  • Static structure-based computational protein design to increase CaM-RyR2 affinity.
  • Molecular dynamics simulations to guide a dynamic-structure redesign strategy.
  • In vitro binding assays and ex vivo functional assays in cardiomyocytes.

Main Results:

  • Static redesign increased CaM-RyR2 binding but distorted RyR2 peptide and worsened Ca2+ leak.
  • Dynamic-structure redesign preserved CaM's conformational integrity and enhanced RyR2 binding.
  • The dynamic CaM variant reduced pathological Ca2+ leak in a disease model.

Conclusions:

  • Successful CaM redesign necessitates preserving its conformational dynamics, not just increasing binding affinity.
  • Integrating conformational dynamics into protein design enables predictive engineering of flexible protein-protein interactions.
  • This approach holds promise for developing therapeutics targeting Ca2+ signaling pathways and related diseases.