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Physiological Reviews Jul 1999Intracellular Ca2+ is normally maintained at submicromolar levels but increases during many forms of cellular stimulation. This increased Ca2+ binds to receptor proteins... (Review)
Review
Intracellular Ca2+ is normally maintained at submicromolar levels but increases during many forms of cellular stimulation. This increased Ca2+ binds to receptor proteins such as calmodulin (CaM) and alters the cell's metabolism and physiology. Calcium-CaM binds to target proteins and alters their function in such a way as to transduce the Ca2+ signal. Calcium-free or apocalmodulin (ApoCaM) binds to other proteins and has other specific effects. Apocalmodulin has roles in the cell that apparently do not require the ability to bind Ca2+ at all, and these roles appear to be essential for life. Apocalmodulin differs from Ca2+-CaM in its tertiary structure. It binds target proteins differently, utilizing different binding motifs such as the IQ motif and noncontiguous binding sites. Other kinds of binding potentially await discovery. The ApoCaM-binding proteins are a diverse group of at least 15 proteins including enzymes, actin-binding proteins, as well as cytoskeletal and other membrane proteins, including receptors and ion channels. Much of the cellular CaM is bound in a Ca2+-independent manner to membrane structures within the cell, and the proportion bound changes with cell growth and density, suggesting it may be a storage form. Apocalmodulin remains tightly bound to other proteins as subunits and probably hastens the response of these proteins to Ca2+. The overall picture that emerges is that CaM cycles between its Ca2+-bound and Ca2+-free states and in each state binds to different proteins and performs essential functions. Although much of the research focus has been on the roles of Ca2+-CaM, the roles of ApoCaM are equally vital but less well understood.
Topics: Amino Acid Sequence; Animals; Calcium-Binding Proteins; Calmodulin; Humans; Ion Channels; Molecular Sequence Data; Receptors, Cell Surface
PubMed: 10390515
DOI: 10.1152/physrev.1999.79.3.661 -
Biochimica Et Biophysica Acta.... Jul 2019This review aims at giving a rational frame to understand the diversity of EF hand containing calcium binding proteins and their roles, with special focus on three... (Review)
Review
This review aims at giving a rational frame to understand the diversity of EF hand containing calcium binding proteins and their roles, with special focus on three members of this huge protein family, namely calmodulin, troponin C and parvalbumin. We propose that these proteins are members of structured macromolecular complexes, termed calcisomes, which constitute building devices allowing treatment of information within eukaryotic cells and namely calcium signals encoding and decoding, as well as control of cytosolic calcium levels in resting cells. Calmodulin is ubiquitous, present in all eukaryotic cells, and pleiotropic. This may be explained by its prominent role in regulating calcium movement in and out of the cell, thus maintaining calcium homeostasis which is fundamental for cell survival. The protein is further involved in decoding transient calcium signals associated with calcium movements after cell stimulation. We will show that the specificity of calmodulin's actions may be more easily explained if one considers its role in the light of calcisomes. Parvalbumin should not be considered as a simple intracellular calcium buffer. It is also a key factor for regulating calcium homeostasis in specific cells that need a rapid retrocontrol of calcium transients, such as fast muscle fibers. Finally, we propose that troponin C, with its four calcium binding domains distributed between two lobes presenting different calcium binding kinetics, exhibits all the characteristics needed to trigger and then post modulate muscle contraction and thus appears as a typical Feed Forward Loop system. If the present conjectures prove accurate, the way will be paved for a new pharmacology targeting the cell calcium signaling machinery. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
Topics: Animals; Calcium; Calcium Signaling; Calmodulin; Humans; Parvalbumins; Troponin C
PubMed: 30716407
DOI: 10.1016/j.bbamcr.2019.01.014 -
International Journal of Molecular... Oct 2020The integral role of calmodulin in the amyloid pathway and neurofibrillary tangle formation in Alzheimer's disease was first established leading to the "Calmodulin... (Review)
Review
The integral role of calmodulin in the amyloid pathway and neurofibrillary tangle formation in Alzheimer's disease was first established leading to the "Calmodulin Hypothesis". Continued research has extended our insight into the central function of the small calcium sensor and effector calmodulin and its target proteins in a multitude of other events associated with the onset and progression of this devastating neurodegenerative disease. Calmodulin's involvement in the contrasting roles of calcium/CaM-dependent kinase II (CaMKII) and calcineurin (CaN) in long term potentiation and depression, respectively, and memory impairment and neurodegeneration are updated. The functions of the proposed neuronal biomarker neurogranin, a calmodulin binding protein also involved in long term potentiation and depression, is detailed. In addition, new discoveries into calmodulin's role in regulating glutamate receptors (mGluR, NMDAR) are overviewed. The interplay between calmodulin and amyloid beta in the regulation of PMCA and ryanodine receptors are prime examples of how the buildup of classic biomarkers can underly the signs and symptoms of Alzheimer's. The role of calmodulin in the function of stromal interaction molecule 2 (STIM2) and adenosine A2A receptor, two other proteins linked to neurodegenerative events, is discussed. Prior to concluding, an analysis of how targeting calmodulin and its binding proteins are viable routes for Alzheimer's therapy is presented. In total, calmodulin and its binding proteins are further revealed to be central to the onset and progression of Alzheimer's disease.
Topics: Alzheimer Disease; Calcium; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Calmodulin-Binding Proteins; Humans; Neurogranin; Neurons; Receptor, Adenosine A2A; Receptors, Glutamate; Stromal Interaction Molecule 2
PubMed: 33027906
DOI: 10.3390/ijms21197344 -
Biochimica Et Biophysica Acta Jul 2013Calcium is a universal messenger involved in the modulation of diverse developmental and adaptive processes in response to various physiological stimuli. Ca(2+) signals... (Review)
Review
Calcium is a universal messenger involved in the modulation of diverse developmental and adaptive processes in response to various physiological stimuli. Ca(2+) signals are represented by stimulus-specific Ca(2+) signatures that are sensed and translated into proper cellular responses by diverse Ca(2+) binding proteins and their downstream targets. Calmodulin (CaM) and calmodulin-like (CML) proteins are primary Ca(2+) sensors that control diverse cellular functions by regulating the activity of various target proteins. Recent advances in our understanding of Ca(2+)/CaM-mediated signalling in plants have emerged from investigations into plant defence responses against various pathogens. Here, we focus on significant progress made in the identification of CaM/CML-regulated components involved in the generation of Ca(2+) signals and Ca(2+)-dependent regulation of gene expression during plant immune responses. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
Topics: Calcium; Calmodulin; Gene Expression Regulation, Plant; Plant Diseases; Plant Immunity; Plant Proteins; Signal Transduction
PubMed: 23380707
DOI: 10.1016/j.bbamcr.2013.01.031 -
The FEBS Journal Nov 2013Calmodulin is the primary sensor of intracellular calcium (Ca(2+)) levels in eukaryotic cells playing a key role in the proper deciphering of Ca(2+) signalling. Given... (Review)
Review
Calmodulin is the primary sensor of intracellular calcium (Ca(2+)) levels in eukaryotic cells playing a key role in the proper deciphering of Ca(2+) signalling. Given the versatility of Ca(2+) as a secondary messenger, it is not surprising that calmodulin interacts with a vast number of proteins. Calmodulin is an extraordinarily conserved protein, which has not evolved since the genesis of the vertebrate lineage, and further is encoded by three different non-allelic genes in the human genome. The protein displays a high degree of conformational plasticity, allowing for target proteins to evolve specific modes of calmodulin interaction and regulation during Ca(2+) sensing. The recent identification of two calmodulin mutations giving rise to a heart arrhythmia with catecholaminergic polymorphic ventricular tachycardia-like symptoms and sudden cardiac death in young individuals, and the following identification of another three calmodulin mutations linked to recurrent cardiac arrest in infants, is in many ways intriguing. How can mutations result in cardiac-specific phenotypes when calmodulin is fundamental for correct Ca(2+) signal interpretation in virtually all cells in vertebrate organisms? Are there specific cardiac target protein interactions that are affected by these mutations? Another challenge is to elucidate how one mutated allele out of six encoding an identical calmodulin protein results in a dominant phenotype. Here we aim to give an overview of components in the cardiac contraction cycle whose function is modulated by calmodulin. In principle, these may all be implicated in the pathogenic molecular mechanism linking calmodulin mutations to cardiac arrhythmia and sudden cardiac death.
Topics: Animals; Arrhythmias, Cardiac; Calcium; Calmodulin; Humans; Muscle Contraction; Mutation
PubMed: 23663249
DOI: 10.1111/febs.12337 -
FEBS Letters Mar 2022Calmodulin is a conserved calcium signalling protein that regulates a wide range of cellular functions. Amino-terminal acetylation is a ubiquitous post-translational...
Calmodulin is a conserved calcium signalling protein that regulates a wide range of cellular functions. Amino-terminal acetylation is a ubiquitous post-translational modification that affects the majority of human proteins, to stabilise structure, as well as regulate function and proteolytic degradation. Here, we present data on the impact of amino-terminal acetylation upon structure and calcium signalling function of fission yeast calmodulin. We show that NatA-dependent acetylation stabilises the helical structure of the Schizosaccharomyces pombe calmodulin, impacting its ability to associate with myosin at endocytic foci. We go on to show that this conserved modification impacts both the calcium-binding capacity of yeast and human calmodulins. These findings have significant implications for research undertaken into this highly conserved essential protein.
Topics: Acetylation; Calcium; Calmodulin; Humans; Protein Processing, Post-Translational; Saccharomyces cerevisiae; Schizosaccharomyces; Schizosaccharomyces pombe Proteins
PubMed: 35100446
DOI: 10.1002/1873-3468.14304 -
International Journal of Molecular... Jan 2019Calmodulin (CaM) is the principal Ca sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes... (Review)
Review
Calmodulin (CaM) is the principal Ca sensor in eukaryotic cells, orchestrating the activity of hundreds of proteins. Disease causing mutations at any of the three genes that encode identical CaM proteins lead to major cardiac dysfunction, revealing the importance in the regulation of excitability. In turn, some mutations at the CaM binding site of ion channels cause similar diseases. Here we provide a summary of the two sides of the partnership between CaM and ion channels, describing the diversity of consequences of mutations at the complementary CaM binding domains.
Topics: Animals; Calcium; Calcium Signaling; Calmodulin; Disease Susceptibility; Gene Expression Regulation; Humans; Ion Channel Gating; Ion Channels; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Sensitivity and Specificity; Signal Transduction; Structure-Activity Relationship
PubMed: 30669290
DOI: 10.3390/ijms20020400 -
The Journal of Biological Chemistry Oct 2021The formation of new memories appears to require alterations in the shape and strength of synapses within the hippocampus, yet our knowledge of the molecular mechanisms...
The formation of new memories appears to require alterations in the shape and strength of synapses within the hippocampus, yet our knowledge of the molecular mechanisms underlying these changes remains incomplete. Zhang and colleagues provide new understanding of memory formation by uncovering the lysine acetyltransferase SRC3 as the key driver of the novel posttranslational modification of calmodulin (CaM) acetylation, which regulates CaM's activity and subsequent activation of CaMKII. This new pathway is demonstrated to be both necessary and sufficient for CA3→CA1 synapse long-term potentiation (LTP) and fear memory formation, and this approach may act as a blueprint for future investigation of the role of acetylation of other proteins in neuronal functions.
Topics: Acetylation; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Hippocampus; Long-Term Potentiation; Protein Processing, Post-Translational; Synapses
PubMed: 34606826
DOI: 10.1016/j.jbc.2021.101273 -
Molecules (Basel, Switzerland) Oct 2022In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin...
In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide compounds are drug prototypes derived from , an alkaloid with activity for cancer treatment. Bisindolylmaleimide compounds II, IV, VII, X, and XI, are proposed and reported as possible inhibitors of calmodulin protein for the first time. For the above, a biotechnological device was used (fluorescent biosensor CaM M124C-) to directly determine binding parameters experimentally ( and stoichiometry) of these compounds, and molecular modeling tools (Docking, Molecular Dynamics, and Chemoinformatic Analysis) to carry out the theoretical studies and complement the experimental data. The results indicate that this compound binds to calmodulin with a between 193-248 nM, an order of magnitude lower than most classic inhibitors. On the other hand, the theoretical studies support the experimental results, obtaining an acceptable correlation between the ΔG and ΔG (r = 0.703) and providing us with complementary molecular details of the interaction between the calmodulin protein and the Bisindolylmaleimide series. Chemoinformatic analyzes bring certainty to Bisindolylmaleimide compounds to address clinical steps in drug development. Thus, these results make these compounds attractive to be considered as possible prototypes of new calmodulin protein inhibitors.
Topics: Calmodulin; Ligands; Biofilms; Bioreactors; Molecular Dynamics Simulation; Protein Binding
PubMed: 36363988
DOI: 10.3390/molecules27217161 -
BMC Biology Aug 2022Calmodulin (CaM) is an evolutionarily conserved eukaryotic multifunctional protein that functions as the major sensor of intracellular calcium signaling. Its...
BACKGROUND
Calmodulin (CaM) is an evolutionarily conserved eukaryotic multifunctional protein that functions as the major sensor of intracellular calcium signaling. Its calcium-modulated function regulates the activity of numerous effector proteins involved in a variety of physiological processes in diverse organs, from proliferation and apoptosis, to memory and immune responses. Due to the pleiotropic roles of CaM in normal and pathological cell functions, CaM antagonists are needed for fundamental studies as well as for potential therapeutic applications. Calmidazolium (CDZ) is a potent small molecule antagonist of CaM and one the most widely used inhibitors of CaM in cell biology. Yet, CDZ, as all other CaM antagonists described thus far, also affects additional cellular targets and its lack of selectivity hinders its application for dissecting calcium/CaM signaling. A better understanding of CaM:CDZ interaction is key to design analogs with improved selectivity. Here, we report a molecular characterization of CaM:CDZ complexes using an integrative structural biology approach combining SEC-SAXS, X-ray crystallography, HDX-MS, and NMR.
RESULTS
We provide evidence that binding of a single molecule of CDZ induces an open-to-closed conformational reorientation of the two domains of CaM and results in a strong stabilization of its structural elements associated with a reduction of protein dynamics over a large time range. These CDZ-triggered CaM changes mimic those induced by CaM-binding peptides derived from physiological protein targets, despite their distinct chemical natures. CaM residues in close contact with CDZ and involved in the stabilization of the CaM:CDZ complex have been identified.
CONCLUSION
Our results provide molecular insights into CDZ-induced dynamics and structural changes of CaM leading to its inhibition and open the way to the rational design of more selective CaM antagonists. Calmidazolium is a potent and widely used inhibitor of calmodulin, a major mediator of calcium-signaling in eukaryotic cells. Structural characterization of calmidazolium-binding to calmodulin reveals that it triggers open-to-closed conformational changes similar to those induced by calmodulin-binding peptides derived from enzyme targets. These results provide molecular insights into CDZ-induced dynamics and structural changes of CaM leading to its inhibition and open the way to the rational design of more selective CaM antagonists.
Topics: Calcium; Calmodulin; Imidazoles; Protein Binding; Scattering, Small Angle; X-Ray Diffraction
PubMed: 35945584
DOI: 10.1186/s12915-022-01381-5