Calmodulin

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Calmodulin
Calmodulin.png
3D structure of Ca2+-bound calmodulin ( PDB: 1OSA ​)
Identifiers
SymbolCaM
PDB 1OSA
UniProt P62158
Search for
Structures Swiss-model
Domains InterPro
The helix-loop-helix structure of the calcium-binding EF hand motif EFhandmotif.jpg
The helix–loop–helix structure of the calcium-binding EF hand motif

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. [1] It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases. [2] [3] [4]

Contents

Structure

Calmodulin is a small, highly conserved protein that is 148 amino acids long (16.7 kDa). The protein has two approximately symmetrical globular domains (the N- and C- domains) each containing a pair of EF hand motifs [5] separated by a flexible linker region for a total of four Ca2+ binding sites, two in each globular domain. [6] In the Ca2+-free state, the helices that form the four EF-hands are collapsed in a compact orientation, and the central linker is disordered; [5] [6] [7] [8] in the Ca2+-saturated state, the EF-hand helices adopt an open orientation roughly perpendicular to one another, and the central linker forms an extended alpha-helix in the crystal structure, [5] [6] but remains largely disordered in solution. [9] The C-domain has a higher binding affinity for Ca2+ than the N-domain. [10] [11]

Calmodulin is structurally quite similar to troponin C, another Ca2+-binding protein containing four EF-hand motifs. [5] [12] However, troponin C contains an additional alpha-helix at its N-terminus, and is constitutively bound to its target, troponin I. It therefore does not exhibit the same diversity of target recognition as does calmodulin.

Importance of flexibility in calmodulin

Calmodulin's ability to recognize a tremendous range of target proteins is due in large part to its structural flexibility. [13] In addition to the flexibility of the central linker domain, the N- and C-domains undergo open-closed conformational cycling in the Ca2+-bound state. [9] Calmodulin also exhibits great structural variability, and undergoes considerable conformational fluctuations, when bound to targets. [14] [15] [16] Moreover, the predominantly hydrophobic nature of binding between calmodulin and most of its targets allows for recognition of a broad range of target protein sequences. [14] [17] Together, these features allow calmodulin to recognize some 300 target proteins [18] exhibiting a variety of CaM-binding sequence motifs.

Mechanism

This images shows conformational changes in calmodulin. On the left is calmodulin without calcium and on the right is calmodulin with calcium. Sites that bind target proteins are indicated by red stars. Calmodulin Binding sites.gif
This images shows conformational changes in calmodulin. On the left is calmodulin without calcium and on the right is calmodulin with calcium. Sites that bind target proteins are indicated by red stars.
Solution structure of Ca -calmodulin C-terminal domain Calmodulin C-terminal.jpg
Solution structure of Ca -calmodulin C-terminal domain
Solution structure of Ca -calmodulin N-terminal domain Calmodulin N-terminal.jpg
Solution structure of Ca -calmodulin N-terminal domain

Binding of Ca2+ by the EF-hands causes an opening of the N- and C-domains, which exposes hydrophobic target-binding surfaces. [6] These surfaces interact with complementary nonpolar segments on target proteins, typically consisting of groups of bulky hydrophobic amino acids separated by 10–16 polar and/or basic amino acids. [18] [14] The flexible central domain of calmodulin allows the protein to wrap around its target, although alternate modes of binding are known. "Canonical" targets of calmodulin, such as myosin light-chain kinases and CaMKII, bind only to the Ca2+-bound protein, whereas some proteins, such as NaV channels and IQ-motif proteins, also bind to calmodulin in the absence of Ca2+. [14] Binding of calmodulin induces conformational rearrangements in the target protein via "mutually induced fit", [19] leading to changes in the target protein's function.

Calcium binding by calmodulin exhibits considerable cooperativity, [5] [11] making calmodulin an unusual example of a monomeric (single-chain) cooperative binding protein. Furthermore, target binding alters the binding affinity of calmodulin toward Ca2+ ions, [20] [21] [22] which allows for complex allosteric interplay between Ca2+ and target binding interactions. [23] This influence of target binding on Ca2+ affinity is believed to allow for Ca2+ activation of proteins that are constitutively bound to calmodulin, such as small-conductance Ca2+-activated potassium (SK) channels. [24]

Although calmodulin principally operates as a Ca2+ binding protein, it also coordinates other metal ions. For example, in the presence of typical intracellular concentrations of Mg2+ (0.5–1.0 mM) and resting concentrations of Ca2+ (100 nM), calmodulin's Ca2+ binding sites are at least partially saturated by Mg2+. [25] This Mg2+ is displaced by the higher concentrations of Ca2+ generated by signaling events. Similarly, Ca2+ may itself be displaced by other metal ions, such as the trivalent lanthanides, that associate with calmodulin's binding pockets even more strongly than Ca2+. [26] [27] Though such ions distort calmodulin's structure [28] [29] and are generally not physiologically relevant due to their scarcity in vivo, they have nonetheless seen wide scientific use as reporters of calmodulin structure and function. [30] [31] [26]

Role in animals

Calmodulin mediates many crucial processes such as inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, and the immune response. [32] [33] Calcium participates in an intracellular signaling system by acting as a diffusible second messenger to the initial stimuli. It does this by binding various targets in the cell including a large number of enzymes, ion channels, aquaporins and other proteins. [4] Calmodulin is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes, but it is always found intracellularly. [33] Many of the proteins that calmodulin binds are unable to bind calcium themselves, and use calmodulin as a calcium sensor and signal transducer. Calmodulin can also make use of the calcium stores in the endoplasmic reticulum, and the sarcoplasmic reticulum. Calmodulin can undergo post-translational modifications, such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which has potential to modulate its actions.

Specific examples

Role in smooth muscle contraction

Calmodulin bound to a peptide from MLC kinase (PDB: 2LV6 ) Calmodulin bound to MLC Kinase.jpg
Calmodulin bound to a peptide from MLC kinase ( PDB: 2LV6 ​)

Calmodulin plays an important role in excitation contraction (EC) coupling and the initiation of the cross-bridge cycling in smooth muscle, ultimately causing smooth muscle contraction. [34] In order to activate contraction of smooth muscle, the head of the myosin light chain must be phosphorylated. This phosphorylation is done by myosin light chain (MLC) kinase. This MLC kinase is activated by a calmodulin when it is bound by calcium, thus making smooth muscle contraction dependent on the presence of calcium, through the binding of calmodulin and activation of MLC kinase. [34]

Another way that calmodulin affects muscle contraction is by controlling the movement of Ca2+ across both the cell and sarcoplasmic reticulum membranes. The Ca2+ channels, such as the ryanodine receptor of the sarcoplasmic reticulum, can be inhibited by calmodulin bound to calcium, thus affecting the overall levels of calcium in the cell. [35] Calcium pumps take calcium out of the cytoplasm or store it in the endoplasmic reticulum and this control helps regulate many downstream processes.

This is a very important function of calmodulin because it indirectly plays a role in every physiological process that is affected by smooth muscle contraction such as digestion and contraction of arteries (which helps distribute blood and regulate blood pressure). [36]

Role in metabolism

Calmodulin plays an important role in the activation of phosphorylase kinase, which ultimately leads to glucose being cleaved from glycogen by glycogen phosphorylase. [37]

Calmodulin also plays an important role in lipid metabolism by affecting calcitonin. Calcitonin is a polypeptide hormone that lowers blood Ca2+ levels and activates Gs protein cascades that leads to the generation of cAMP. The actions of calcitonin can be blocked by inhibiting the actions of calmodulin, suggesting that calmodulin plays a crucial role in the activation of calcitonin. [37]

Role in short-term and long-term memory

Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a crucial role in a type of synaptic plasticity known as long-term potentiation (LTP) which requires the presence of calcium/calmodulin. CaMKII contributes to the phosphorylation of an AMPA receptor which increases the sensitivity of AMPA receptors. [38] Furthermore, research shows that inhibiting CaMKII interferes with LTP. [38]

Role in plants

Sorghum plant contains temperature-responsive genes. These genes help the plant adapt in extreme weather conditions such as hot and dry environments. Sorghum bicolor (4171536532).jpg
Sorghum plant contains temperature-responsive genes. These genes help the plant adapt in extreme weather conditions such as hot and dry environments.

While yeasts have only a single CaM gene, plants and vertebrates contain an evolutionarily conserved form of CaM genes. The difference between plants and animals in Ca2+ signaling is that the plants contain an extended family of the CaM in addition to the evolutionarily conserved form. [39] Calmodulins play an essential role in plant development and adaptation to environmental stimuli.

Calcium plays a key role in the structural integrity of the cell wall and the membrane system of the cell. However, high calcium levels can be toxic to a plant's cellular energy metabolism and, hence, the Ca2+ concentration in the cytosol is maintained at a submicromolar level by removing the cytosolic Ca2+ to either the apoplast or the lumen of the intracellular organelles. Ca2+ pulses created due to increased influx and efflux act as cellular signals in response to external stimuli such as hormones, light, gravity, abiotic stress factors and also interactions with pathogens. [40]

Plants contain CaM-related proteins (CMLs) apart from the typical CaM proteins. The CMLs have about 15% amino acid similarity with the typical CaMs. Arabidopsis thaliana contains about 50 different CML genes, [41] which leads to the question of what purpose these diverse ranges of proteins serve in the cellular function. All plant species exhibit this diversity in the CML genes. The different CaMs and CMLs differ in their affinity to bind and activate the CaM-regulated enzymes in vivo. The CaM or CMLs are also found to be located in different organelle compartments.

Plant growth and development

In Arabidopsis, the protein DWF1 plays an enzymatic role in the biosynthesis of brassinosteroids, steroid hormones in plants that are required for growth. An interaction occurs between CaM and DWF1,[ clarification needed ] and DWF1 being unable to bind CaM is unable to produce a regular growth phenotype in plants. Hence, CaM is essential for the DWF1 function in plant growth.

CaM binding proteins are also known to regulate reproductive development in plants. For instance, the CaM-binding protein kinase in tobacco acts as a negative regulator of flowering. However, these CaM-binding protein kinase are also present in the shoot apical meristem of tobacco and a high concentration of these kinases in the meristem causes a delayed transition to flowering in the plant.

S-locus receptor kinase (SRK) is another protein kinase that interacts with CaM. SRK is involved in the self-incompatibility responses involved in pollen-pistil interactions in Brassica .

CaM targets in Arabidopsis are also involved in pollen development and fertilization. Ca2+ transporters are essential for pollen tube growth. Hence, a constant Ca2+ gradient is maintained at the apex of pollen tube for elongation during the process of fertilization. Similarly, CaM is also essential at the pollen tube apex, where its primarily role involves the guidance of the pollen tube growth.

Interaction with microbes

Nodule formation

Ca2+ plays an important role in nodule formation in legumes. Nitrogen is an essential element required in plants and many legumes, unable to fix nitrogen independently, pair symbiotically with nitrogen-fixing bacteria that reduce nitrogen to ammonia. This legume- Rhizobium interaction establishment requires the Nod factor that is produced by the Rhizobium bacteria. The Nod factor is recognized by the root hair cells that are involved in the nodule formation in legumes. Ca2+ responses of varied nature are characterized to be involved in the Nod factor recognition. There is a Ca2+ flux at the tip of the root hair initially followed by repetitive oscillation of Ca2+ in the cytosol and also Ca2+ spike occurs around the nucleus. DMI3, an essential gene for Nod factor signaling functions downstream of the Ca2+ spiking signature, might be recognizing the Ca2+ signature. Further, several CaM and CML genes in Medicago and Lotus are expressed in nodules.

Pathogen defense

Among the diverse range of defense strategies plants utilize against pathogens, Ca2+ signaling is very common. Free Ca2+ levels in the cytoplasm increases in response to a pathogenic infection. Ca2+ signatures of this nature usually activate the plant defense system by inducing defense-related genes and the hypersensitive cell death. CaMs, CMLs and CaM-binding proteins are some of the recently identified elements of the plant defense signaling pathways. Several CML genes in tobacco, bean and tomato are responsive to pathogens. CML43 is a CaM-related protein that, as isolated from APR134 gene in the disease-resistant leaves of Arabidopsis for gene expression analysis, is rapidly induced when the leaves are inoculated with Pseudomonas syringae . These genes are also found in tomatoes (Solanum lycopersicum). The CML43 from the APR134 also binds to Ca2+ ions in vitro which shows that CML43 and APR134 are, hence, involved in the Ca2+-dependent signaling during the plant immune response to bacterial pathogens. [42] The CML9 expression in Arabidopsis thaliana is rapidly induced by phytopathogenic bacteria, flagellin and salicylic acid. [43] Expression of soybean SCaM4 and SCaM5 in transgenic tobacco and Arabidopsis causes an activation of genes related to pathogen resistance and also results in enhanced resistance to a wide spectrum of pathogen infection. The same is not true for soybean SCaM1 and SCaM2 that are highly conserved CaM isoforms. The AtBAG6 protein is a CaM-binding protein that binds to CaM only in the absence of Ca2+ and not in the presence of it. AtBAG6 is responsible for the hypersensitive response of programmed cell death in order to prevent the spread of pathogen infection or to restrict pathogen growth. Mutations in the CaM binding proteins can lead to severe effects on the defense response of the plants towards pathogen infections. Cyclic nucleotide-gated channels (CNGCs) are functional protein channels in the plasma membrane that have overlapping CaM binding sites transport divalent cations such as Ca2+. However, the exact role of the positioning of the CNGCs in this pathway for plant defense is still unclear.

Abiotic stress response in plants

Change in intracellular Ca2+ levels is used as a signature for diverse responses towards mechanical stimuli, osmotic and salt treatments, and cold and heat shocks. Different root cell types show a different Ca2+ response to osmotic and salt stresses and this implies the cellular specificities of Ca2+ patterns. In response to external stress CaM activates glutamate decarboxylase (GAD) that catalyzes the conversion of L-glutamate to GABA. A tight control on the GABA synthesis is important for plant development and, hence, increased GABA levels can essentially affect plant development. Therefore, external stress can affect plant growth and development and CaM are involved in that pathway controlling this effect.[ citation needed ]

Plant examples

Sorghum

The plant sorghum is well established model organism and can adapt in hot and dry environments. For this reason, it is used as a model to study calmodulin's role in plants. [44] Sorghum contains seedlings that express a glycine-rich RNA-binding protein, SbGRBP. This particular protein can be modulated by using heat as a stressor. Its unique location in the cell nucleus and cytosol demonstrates interaction with calmodulin that requires the use of Ca2+. [45] By exposing the plant to versatile stress conditions, it can cause different proteins that enable the plant cells to tolerate environmental changes to become repressed. These modulated stress proteins are shown to interact with CaM. The CaMBP genes expressed in the sorghum are depicted as a “model crop” for researching the tolerance to heat and drought stress.

Arabidopsis

In an Arabidopsis thaliana study, hundreds of different proteins demonstrated the possibility to bind to CaM in plants. [44]

Family members

Other calcium-binding proteins

Calmodulin belongs to one of the two main groups of calcium-binding proteins, called EF hand proteins. The other group, called annexins, bind calcium and phospholipids such as lipocortin. Many other proteins bind calcium, although binding calcium may not be considered their principal function in the cell.

See also

Related Research Articles

<span class="mw-page-title-main">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g. muscle, glial cells, neurons) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the enzymes transfer phosphates from ATP to defined serine or threonine residues in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and therefore, in the regulation of expression of responding genes. CAMK also works to regulate the cell life cycle (i.e. programmed cell death), rearrangement of the cell's cytoskeletal network, and mechanisms involved in the learning and memory of an organism.

<span class="mw-page-title-main">Calcium signaling</span> Intracellular communication process

Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.

Thigmomorphogenesis the phenomenon by which plants alter their growth and development in response to mechanical stimuli, exemplifies their remarkable adaptability to fluctuating environmental conditions. From subtle forces such as wind or rain to deliberate touch, these stimuli trigger a cascade of cellular and molecular responses, shaping plant architecture to optimize survival and ecological fitness. Botanists first observed these changes when greenhouse-grown plants were found to be taller and more slender compared to stockier plants grown outdoors, where they were exposed to natural mechanical stresses. At its core, thigmomorphogenesis involves the perception of mechanical forces by cellular mechanosensors, their transduction into biochemical signals, and subsequent changes in gene expression and hormone activity. This response integrates diverse molecular players, including mechanosensitive ion channels, receptor-like kinases, cytoskeletal elements, phytohormones, and transcription factors, which collectively drive both immediate and long-term morphological adaptations.

<span class="mw-page-title-main">Myosin light-chain kinase</span> Class of kinase enzymes

Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.

Calmodulin-binding proteins are, as their name implies, proteins which bind calmodulin. Calmodulin can bind to a variety of proteins through a two-step binding mechanism, namely "conformational and mutually induced fit", where typically two domains of calmodulin wrap around an emerging helical calmodulin binding domain from the target protein.

<span class="mw-page-title-main">EF hand</span> Protein helix–loop–helix motif

The EF hand is a helix–loop–helix structural domain or motif found in a large family of calcium-binding proteins.

Calcium-binding proteins are proteins that participate in calcium cell signaling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to calcium and are known to be heterogeneous.

Ca<sup>2+</sup>/calmodulin-dependent protein kinase II Class of enzymes

Ca2+
/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
 homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.

<span class="mw-page-title-main">L-type calcium channel</span> Family of transport proteins

The L-type calcium channel is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

<span class="mw-page-title-main">Wall-associated kinase</span>

Wall-associated kinases (WAKs) are one of many classes of plant proteins known to serve as a medium between the extracellular matrix (ECM) and cytoplasm of cell walls. They are serine-threonine kinases that contain epidermal growth factor (EGF) repeats, a cytoplasmic kinase and are located in the cell walls. They provide a linkage between the inner and outer surroundings of cell walls. WAKs are under a group of receptor-like kinases (RLK) that are actively involved in sensory and signal transduction pathways especially in response to foreign attacks by pathogens and in cell development. On the other hand, pectins are an abundant group of complex carbohydrates present in the primary cell wall that play roles in cell growth and development, protection, plant structure and water holding capacity.

<span class="mw-page-title-main">Calmodulin 1</span> Protein found in humans

Calmodulin 1 is a protein in humans that is encoded by the CALM1 gene.

In enzymology, an elongation factor 2 kinase is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">Inositol-trisphosphate 3-kinase</span> Class of enzymes

Inositol (1,4,5) trisphosphate 3-kinase (EC 2.7.1.127), abbreviated here as ITP3K, is an enzyme that facilitates a phospho-group transfer from adenosine triphosphate to 1D-myo-inositol 1,4,5-trisphosphate. This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with an alcohol group as acceptor. The systematic name of this enzyme class is ATP:1D-myo-inositol-1,4,5-trisphosphate 3-phosphotransferase. ITP3K catalyzes the transfer of the gamma-phosphate from ATP to the 3-position of inositol 1,4,5-trisphosphate to form inositol 1,3,4,5-tetrakisphosphate. ITP3K is highly specific for the 1,4,5-isomer of IP3, and it exclusively phosphorylates the 3-OH position, producing Ins(1,3,4,5)P4, also known as inositol tetrakisphosphate or IP4.

<span class="mw-page-title-main">Troponin C type 1</span> Protein-coding gene in the species Homo sapiens

Troponin C, also known as TN-C or TnC, is a protein that resides in the troponin complex on actin thin filaments of striated muscle and is responsible for binding calcium to activate muscle contraction. Troponin C is encoded by the TNNC1 gene in humans for both cardiac and slow skeletal muscle.

<span class="mw-page-title-main">CAMK1</span> Protein-coding gene in humans

Calcium/calmodulin-dependent protein kinase type 1 is an enzyme that in humans is encoded by the CAMK1 gene.

<span class="mw-page-title-main">EEF2K</span> Protein-coding gene in humans

Eukaryotic elongation factor-2 kinase, also known as calmodulin-dependent protein kinase III (CAMKIII) and calcium/calmodulin-dependent eukaryotic elongation factor 2 kinase, is an enzyme that in humans is encoded by the EEF2K gene.

<span class="mw-page-title-main">Calcium-binding protein 1</span> Protein found in humans

Calcium binding protein 1 is a protein that in humans is encoded by the CABP1 gene. Calcium-binding protein 1 is a calcium-binding protein discovered in 1999. It has two EF hand motifs and is expressed in neuronal cells in such areas as hippocampus, habenular nucleus of the epithalamus, Purkinje cell layer of the cerebellum, and the amacrine cells and cone bipolar cells of the retina.

Calcium signaling in <i>Arabidopsis</i>

Calcium signaling in Arabidopsis is a calcium mediated signalling pathway that Arabidopsis plants use in order to respond to a stimuli. In this pathway, Ca2+ works as a long range communication ion, allowing for rapid communication throughout the plant. Systemic changes in metabolites such as glucose and sucrose takes a few minutes after the stimulus, but gene transcription occurs within seconds. Because hormones, peptides and RNA travel through the vascular system at lower speeds than the plants response to wounds, indicates that Ca2+ must be involved in the rapid signal propagation. Instead of local communication to nearby cells and tissues, Ca2+ uses mass flow within the vascular system to help with rapid transport throughout the plant. Ca2+ moving through the xylem and phloem acts through a “calcium signature” receptor system in cells where they integrate the signal and respond with the activation of defense genes. These calcium signatures encode information about the stimulus allowing the response of the plant to cater towards the type of stimulus.

References

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