CAMK

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Ca2+/calmodulin-dependent protein kinase
Identifiers
EC no. 2.7.11.17
CAS no. 97350-82-8
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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. [1]

Contents

Types

There are 2 common types of CAM Kinase proteins: specialized and multi-functional CAM kinases.

Substrate-specific CAM Kinases
only have one target that they can phosphorylate, such as myosin light chain kinases. [1] This group of proteins includes CAMK III. More on CAMKIII can be found following this link.
Multi-functional CAM Kinases
have multiple targets they can phosphorylate and are found in processes including the secretion of neurotransmitters, metabolism of glycogen, and the regulation of various transcription factors. [1] CAMK II is the main protein in this subset. More on CAMKII can be found following this link.

Substrate phosphorylation

Figure 1: Diagram of how CAMK II becomes active in the presence of calcium or calmodulin. Psy161ST redrawn.svg
Figure 1: Diagram of how CAMK II becomes active in the presence of calcium or calmodulin.

Once calcium concentrations in the cell rise, CAM kinases become saturated and bind the maximum of four calcium molecules. [1] This calcium saturation activates the kinase and allows it to undergo a conformational change which permits the kinase to bind to its phosphorylation target sites. CAMK removes a phosphate group from ATP, most typically using a Mg2+ ion, and adds it to the CAM protein, rendering it active. [2] The CAM Kinase contains a highly concentrated glycine loop where the gamma phosphate from the donor ATP molecule is easily able to bind to the enzyme which then utilizes the metal ion to facilitate a smooth phosphate transfer to the target protein. [3] This phosphate transfer then activates the kinase's target and completes the phosphorylation cycle.

Figure 1 shows how the presence of calcium or calmodulin allows for the activation of CAM kinases (CAMK II).

Figure 2: Graphic illustration of the crude domains of Calcium/calmodulin-dependent protein kinase 1 CAMK I structure.png
Figure 2: Graphic illustration of the crude domains of Calcium/calmodulin-dependent protein kinase 1

Structure

All kinases have a common structure of a catalytic core including an ATP binding site along with a larger substrate binding site. [4] The catalytic core is typically composed of β-strands with the substrate binding site composed of α-helices. [5] Most all CAM kinases includes a variety of domains, including: a catalytic domain, a regulatory domain, an association domain, and a calcium/calmodulin binding domain. [6]

CAMK I
as shown in Figure 2, has a double-lobed structure, consisting of a catalytic, substrate-binding domain and an autoinhibitory domain. [1] For the autoinhibitory domain to become functional, it must cause the protein to conform in such a way that this domain completely blocks the substrate domain from taking in new targets. Figure 2 goes into detail showing the structure and domains of CAMK I.
CAMK II
has a variety of different forms, with CAMK 2A being the most common, as shown in Figure 3. CAMK 2A has a ring-like crystalline structure, composed of smaller functional groups. These groups allow for the CaM-dependent phosphorylation of targets, but also allows the structure to autophosphorylate itself and become CaM-independent, [7] as seen in Figure 1. This means once the CAMK 2A protein is initially activated by calcium or calmodulin, it can, in turn, further activate itself, so it doesn't become inactive even when it is without calcium or calmodulin.
Figure 3: Image of CAMK 2A which is a form of Calcium/calmodulin-dependent kinase in its crystalline form. PDB 1hkx EBI.jpg
Figure 3: Image of CAMK 2A which is a form of Calcium/calmodulin-dependent kinase in its crystalline form.

Family members

Members of the CAMK enzyme class include, but are not limited to:

Pseudokinases

Pseudokinases are pseudoenzymes, proteins that resemble enzymes structurally, but lack catalytic activity.

Some of these pseudokinases that are related to the CAMK family include:

Related Research Articles

<span class="mw-page-title-main">Protein kinase</span> Enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Calmodulin</span> Messenger protein

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. 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.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

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.

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

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">Phosphorylase kinase</span>

Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformational shift which favors the more active glycogen phosphorylase “a” form over the less active glycogen phosphorylase b.

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

<span class="mw-page-title-main">Calcium/calmodulin-dependent protein kinase type II subunit alpha</span> Protein-coding gene in the species Homo sapiens

Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMKIIα), a.k.a.Ca2+/calmodulin-dependent protein kinase II alpha, is one subunit of CamKII, a protein kinase (i.e., an enzyme which phosphorylates proteins) that in humans is encoded by the CAMK2A gene.

<span class="mw-page-title-main">CAMK4</span> Protein-coding gene in the species Homo sapiens

Calcium/calmodulin-dependent protein kinase type IV is an enzyme that in humans is encoded by the CAMK4 gene.

In enzymology, a ceramide kinase, also abbreviated as CERK, is an enzyme that catalyzes the chemical reaction:

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">CAMK1</span> Protein-coding gene in the species Homo sapiens

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">WNK4</span> Protein-coding gene in the species Homo sapiens

Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome.

<span class="mw-page-title-main">CAMKK1</span> Protein-coding gene in the species Homo sapiens

Calcium/calmodulin-dependent protein kinase kinase 1 is an enzyme that in humans is encoded by the CAMKK1 gene.

<span class="mw-page-title-main">Synapsin I</span> Protein-coding gene in the species Homo sapiens

Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoproteins that in humans are encoded by the SYN1 gene. In its phosphorylated form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia.

References

  1. 1 2 3 4 5 6 Swulius MT, Waxham MN (September 2008). "Ca(2+)/calmodulin-dependent protein kinases". Cellular and Molecular Life Sciences. 65 (17): 2637–57. doi:10.1007/s00018-008-8086-2. PMC   3617042 . PMID   18463790.
  2. ↑ Adams JA (August 2001). "Kinetic and catalytic mechanisms of protein kinases". Chemical Reviews. 101 (8): 2271–90. doi:10.1021/cr000230w. PMID   11749373.
  3. ↑ Hemmer W, McGlone M, Tsigelny I, Taylor SS (July 1997). "Role of the glycine triad in the ATP-binding site of cAMP-dependent protein kinase". The Journal of Biological Chemistry. 272 (27): 16946–54. doi: 10.1074/jbc.272.27.16946 . PMID   9202006. S2CID   33795382.
  4. ↑ Hanks SK (2003). "Genomic analysis of the eukaryotic protein kinase superfamily: a perspective". Genome Biology. 4 (5): 111. doi: 10.1186/gb-2003-4-5-111 . PMC   156577 . PMID   12734000.
  5. ↑ Taylor SS, Yang J, Wu J, Haste NM, Radzio-Andzelm E, Anand G (March 2004). "PKA: a portrait of protein kinase dynamics". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1697 (1–2): 259–69. doi:10.1016/j.bbapap.2003.11.029. PMID   15023366.
  6. ↑ Hudmon A, Schulman H (2002-06-01). "Neuronal CA2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function". Annual Review of Biochemistry. 71 (1): 473–510. doi:10.1146/annurev.biochem.71.110601.135410. PMID   12045104.
  7. ↑ "CAMK2A calcium/calmodulin dependent protein kinase II alpha [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-03-20.
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