Inositol-trisphosphate 3-kinase

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Inositol trisphosphate 3-kinase
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Inositol-trisphosphate 3-kinase A Catalytic Core. 1TZD ​
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EC no. 2.7.1.127
CAS no. 106283-10-7
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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. [1] 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.

Contents

In biology, the enzyme ITP3K is abbreviated a number of different ways, including 1D-myo-inositol-trisphosphate 3-kinase, ITP3K, ITPK, IP3-kinase, IP3-3-kinase, Ins(1,4,5)P3 3-kinase. In addition the enzyme may be named as the product of one of 3 genes in humans ITPKA, ITPKB, and ITPKC, or one of two in fruit flies, IP3K1 and IP3K2—a mutant known to geneticists as wavy. [2] The nematode genome has one form of the enzyme, coded by the LFE-2 gene. ITP3K enzymes are expressed only in metazoans; they are not expressed in yeast or plants.

All ITP3Ks belong to a larger structural family, the inositol polyphosphate kinases, or IPKs. Note however, that the human genome also contains a gene for a different kinase known as ITPK1, which is an inositol 1, 3, 4-trisphosphate 5/6-kinase and is not a member of the IPK family.

The ITP3K enzyme family is sometimes confused with a different enzyme family that has a similar name, that is, the phosphatidyl inositol 3-kinases or phosphoinositide 3-kinase (PI3-K),whose substrates are inositol lipids, not the soluble second messenger inositol trisphosphate.

Discovery and characterization

Scientific interest in the inositol phosphates intensified in the years following the 1983 discovery that inositol trisphosphate was an intracellular messenger that releases calcium from intracellular stores in the endoplasmic reticulum. [3] By the end of the decade, a large number of inositol phosphate kinases and phosphatases had been discovered, including ITP3K in 1986. [4] [5] Biochemical and molecular studies in the 1990s led to the purification of the enzyme from rat brain and it molecular cloning, and these studies revealed various feedback mechanisms by which the enzyme is regulated by calcium and protein kinases. [6] In 1999, ITP3K was identified as being a member of a larger family of Inositol polyphosphate kinases, which share a similar structure and catalytic mechanism. [7] [8] ITP3K enzymes share common structural features including a conserved catalytic core which binds ATP located near the C-terminus, and various regulatory domains nearer to the N-terminus. [9]

Catalytic domain

Evidence for this exquisite specificity and for the catalytic mechanism was found when the apo-enzyme, substrate-bound complex, and product-bound complex X-ray crystal structures of ITPKA were determined. [10] [11] The figure to the right depicts the catalytic mechanism, whereby the 3'OH of IP3 attacks the gamma-phosphate of ATP, and amino acid residues of ITPK important for stabilizing the substrates and products in the active site.

Phosphoryl Transfer Reaction Catalyzed by ITP3K. Hydrogen bonds are represented as dotted lines. Select ITP3K amino acids are shown in blue. Red arrows represent electron pushing. A metal cofactor (Mn2+, magenta) and a highly conserved Asp416 are essential for positioning the ATP beta- and gamma-phosphates. Arg319 (among other amino acids that are not shown) is involved in orienting IP3. Lys264 is most likely involved in neutralizing the negative charge that develops on phosphate, and it may also serve as a general base (hydrogen acceptor) for the 3'OH of IP3. ITP3K Catalytic Mechanism.png
Phosphoryl Transfer Reaction Catalyzed by ITP3K. Hydrogen bonds are represented as dotted lines. Select ITP3K amino acids are shown in blue. Red arrows represent electron pushing. A metal cofactor (Mn2+, magenta) and a highly conserved Asp416 are essential for positioning the ATP beta- and gamma-phosphates. Arg319 (among other amino acids that are not shown) is involved in orienting IP3. Lys264 is most likely involved in neutralizing the negative charge that develops on phosphate, and it may also serve as a general base (hydrogen acceptor) for the 3'OH of IP3.

The structure of the catalytic domain of the human ITP3KA has been shown to be divided into three subdomains. These subdomains are displayed as the N lobe, which is a N-terminal domain, the C lobe, which is a C-terminal subdomain and a third alpha-only subdomain. The ITP3K catalytic domain varies somewhat from the protein kinase superfamily, and it has a novel four-helix substrate binding domain. In this kinase, the two domains are in an open conformation, which indicates that the two domains are both accessible at the same time. This suggests that substrate recognition and catalysis by ITP3K involves a dynamic conformational cycle. Additionally, this unique helical domain of ITPK blocks access to the active site by membrane-bound phosphoinositides, explaining the structural basis for soluble inositol polyphosphate specificity. Another feature of the catalytic core is the ATP binding site. Here, one molecule of ADP is bound in the cleft of the major domain, which indicates the active site of the kinase.

In further detail, the larger domain of the protein structure has an α/β-class structure. The domain has an N-terminal and a C-terminal lobe with a cleft in between and each of these lobes is built around an antiparallel β-sheet. In the N-terminal, the sheet has three strands, whereas in the C-terminal there is a five-stranded sheet. The second domain, is α-helical and consists of four α helices linked by long loops. The helices are loosely packed against each other and the entire domain is highly mobile as compared to the large α/β domain. The helical domain is juxtaposed against one end of the cleft in the large domain.

Regulation

ITP3K is regulated by various post-translational mechanisms. ITP3Ks are stimulated directly by calcium/calmodulin (Ca2+/CaM) binding. [12] Generally, mammalian ITP3Ks are activated by calcium and calmodulin to varying degrees. The method in which this works is calmodulin recognizes sequences which contain amphiphilic alpha-helices with clusters of positively charged and hydrophobic amino acids. [13] Certain sequences are required for CaM binding and enzyme activation and this level of stimulation appears to be specific to cell, tissue, or isoform. ITP3Ks from nematodes and Arabidopsis thaliana lack the CaM-binding sites and therefore are insensitive to calcium and calmodulin. [14] Another major post-translational modification that is important for ITP3K regulation is phosphorylation. ITP3K activity is indirectly stimulated by phosphorylation by calcium/calmodulin-dependent kinase II (CaMKII). In addition, there is evidence that ITP3Ks may be activated upon phosphorylation by protein kinase C (PKC) and inhibited upon phosphorylation by protein kinase A (PKA).

Isoforms

There are three ITP3Ks which are encoded by the human genome: ITPKA, ITPKB, and ITPKC. All share a conserved C-terminal catalytic domain, but differ in mechanisms of regulation as well as tissue expression. ITPKA is predominant in neurons and in the testes. It is localized to dendritic spines by an association with filamentous actin which is consistent with its probable role in memory functions. ITPKB is expressed more widely, but it is often enriched in immune tissues, and it has different intracellular localizations that depend on tissue, interaction with actin filaments, and proteolysis at the N-terminal regions. ITPKC is also expressed in many different tissues and it is more enriched in the nucleus compared to the other isoforms.

Functions in Calcium Signaling

ITP3K plays a role in regulating or cooperating with intracellular calcium signals that occur following the liberation of inositol trisphosphate. In this pathway, either a G-protein coupled receptor (GPCR) or receptor tyrosine kinase (RTK) is activated by an extracellular ligand-binding event. Initiation of the pathway leads to an activated G-alpha subunit of a heterotrimeric G protein (in the case of GPCR-mediated signal transduction) or autophoshorylation of RTK cytoplasmic domains (in the case of RTK-mediated signal transduction). These intracellular events eventually lead to activation of phospholipase C (PLC), which cleaves the phospholipid PIP2 into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG remains associated with the plasma membrane, while IP3 is released into the cytoplasm. IP3 then diffuses through the cytosol and binds to IP3 receptors on the endoplasmic reticulum or sarcoplasmic reticulum, resulting in the opening of a membrane channel and an influx of calcium ions into the cytoplasm. [15] Calcium serves as a second messenger for various downstream cellular events including glycogen metabolism, muscle contraction, neurotransmitter release, and transcriptional regulation. [15] Therefore, calcium homeostasis is essential for proper cell function and response to extracellular signals. [16]

In order to prepare the cell for a future signaling event, the calcium pathway must be tightly regulated. ITP3K seems to play an important role in termination of the signal. As mentioned, ITP3K catalyzes the phosphorylation of IP3 to make IP4. Unlike IP3, IP4 does not cause opening of calcium channels on the endoplasmic reticulum or sarcoplasmic reticulum. [17] By decreasing the concentration of IP3 in the cytoplasm, ITP3K terminates propagation of the calcium signaling pathway. [14]

The calcium signaling pathway is involved in a variety of cellular processes including muscle contraction, gamete fertilization, and neurotransmitter release. Since the calcium second messenger has such widespread cellular functionality, it must be tightly regulated. ITP3K, shown in step 6 in the schematic, plays a role in calcium homeostasis by means of signal termination. Calcium Signaling Pathway.png
The calcium signaling pathway is involved in a variety of cellular processes including muscle contraction, gamete fertilization, and neurotransmitter release. Since the calcium second messenger has such widespread cellular functionality, it must be tightly regulated. ITP3K, shown in step 6 in the schematic, plays a role in calcium homeostasis by means of signal termination.

Additional roles

ITP3K is not the only enzyme responsible for clearing IP3 from the cytoplasm. A second enzyme called inositol 5-phosphatase catalyzes the dephosphorylation of IP3 to create IP2. [18] Typically, nature does not favor the evolution of a second enzyme to perform an already-existing, identical function. [19] A closer inspection of the evolutionary history of inositol 5-phosphatase and ITP3K gives rise to several interesting hypotheses about the roles of these enzymes in the cell.

Inositol 5-phosphatase existed before ITP3K evolved in the mammalian cell. Like other phosphatases, inositol 5-phosphatase is an energy-independent enzyme that cleaves a phosphate group off of a substrate. [20] In contrast, ITP3K (like all kinases) is energy-dependent, meaning that it requires an ATP molecule to perform the phosphoryl transfer chemistry. [21] If nature already had an energy-independent mechanism for termination of the calcium signaling pathway, why was the evolution of ITP3K advantageous? This apparent redundancy of function, or "waste" of energy by the cell, suggests that ITP3K may have a more important function in the cell than simply clearing the IP3 second messenger from the cytoplasm. [20] Current hypotheses about additional roles for ITPK are explained in the following two subsections.

Product of ITPK may be a second messenger

As mentioned previously, ITP3K catalyzes a phosphoryl transfer reaction that converts IP3 to IP4. IP4 does not stimulate calcium influx through IP3 receptor channels on the endoplasmic or sarcoplasmic reticulum. However, it has been shown that IP4 stimulates calcium channel opening on the plasma membrane. In this way, IP4 may actually serve to prolong the calcium signal by activating the influx of calcium stores from the extracellular space. In addition, there is evidence that IP4 binds two GTPase-activating proteins, GAP1IP4BP and GAP1m. [18] GAPs are often used in signal transduction as on/off switches. IP4 binding to GAPs suggests that ITPK may be involved in a parallel signal transduction pathway. The exact role of IP4 binding to these GAPs has not been determined, though, so additional research in this area will be needed to gain a more complete understanding. [22]

Role in inositol phosphate metabolism

In addition to its potential roles as a second messenger, IP4 may also function as an essential precursor for other more highly phosphorylated inositol phosphates such as IP5, IP6, IP7, and IP8. Such maintenance is necessary to prepare the cell for a future incoming signal. [22]

Relevance to physiology and human disease

ITPKA protein is highly enriched in dendritic spines. [23] ITPKA participates in learning and memory process in neuronal cells, both via its catalytic activity and its interaction with filamentous actin.

Although ITPKA is expressed physiologically in neurons and testis, the gene becomes expressed in a number of cancer cell types. In most cases, ITP3K expression causes the cancer to be more aggressive. [24]

ITPKB is implicated in physiologic immune function. [25]

ITPKC has been linked to Kawasaki Disease, an autoimmune disorder. [26] [27]

Related Research Articles

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

<span class="mw-page-title-main">Inositol trisphosphate receptor</span> Class of transport proteins

Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiological processes including cell division, cell proliferation, apoptosis, fertilization, development, behavior, learning and memory. Inositol triphosphate receptor represents a dominant second messenger leading to the release of Ca2+ from intracellular store sites. There is strong evidence suggesting that the InsP3R plays an important role in the conversion of external stimuli to intracellular Ca2+ signals characterized by complex patterns relative to both space and time, such as Ca2+ waves and oscillations.

Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.

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">Inositol phosphate</span>

Inositol phosphates are a group of mono- to hexaphosphorylated inositols. Each form of inositol phosphate is distinguished by the number and position of the phosphate group on the inositol ring.

<span class="mw-page-title-main">Phosphoinositide phospholipase C</span>

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<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.

Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred to as Gq alpha, Gαq, or Gqα. Gq proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC).

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

Inositol-trisphosphate 3-kinase B is an enzyme that in humans is encoded by the ITPKB gene.

<span class="mw-page-title-main">ITPR1</span> Protein-coding gene in the species Homo sapiens

Inositol 1,4,5-trisphosphate receptor type 1 is a protein that in humans is encoded by the ITPR1 gene.

<span class="mw-page-title-main">INPP5D</span> Protein-coding gene in the species Homo sapiens

Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1(SHIP1) is an enzyme with phosphatase activity. SHIP1 is structured by multiple domain and is encoded by the INPP5D gene in humans. SHIP1 is expressed predominantly by hematopoietic cells but also, for example, by osteoblasts and endothelial cells. This phosphatase is important for the regulation of cellular activation. Not only catalytic but also adaptor activities of this protein are involved in this process. Its movement from the cytosol to the cytoplasmic membrane, where predominantly performs its function, is mediated by tyrosine phosphorylation of the intracellular chains of cell surface receptors that SHIP1 binds. Insufficient regulation of SHIP1 leads to different pathologies.

<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

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

Inositol-trisphosphate 3-kinase A is an enzyme that in humans is encoded by the ITPKA gene.

<span class="mw-page-title-main">ITPK1</span> Protein-coding gene in the species Homo sapiens

Inositol-tetrakisphosphate 1-kinase is an enzyme that in humans is encoded by the ITPK1 gene.

ITPKC is one of 3 human genes that encode for an Inositol-trisphosphate 3-kinase. This gene that has been associated with Kawasaki disease. Kawasaki disease is an acute febrile illness that involves the inflammation of blood vessels throughout the body. The majority of cases that have been diagnosed involve children under the age of 5. In untreated cases involving children, 15 to 25 percent of these cases developed coronary artery aneurysms. The overproduction of T cells may be correlated with the immune hyperactivity in Kawasaki disease.

<span class="mw-page-title-main">ITPR3</span> Protein-coding gene in the species Homo sapiens

Inositol 1,4,5-trisphosphate receptor, type 3, also known as ITPR3, is a protein which in humans is encoded by the ITPR3 gene. The protein encoded by this gene is both a receptor for inositol triphosphate and a calcium channel.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

The ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family includes Ryanodine receptors and Inositol trisphosphate receptors. Members of this family are large proteins, some exceeding 5000 amino acyl residues in length. This family belongs to the Voltage-gated ion channel (VIC) superfamily. Ry receptors occur primarily in muscle cell sarcoplasmic reticular (SR) membranes, and IP3 receptors occur primarily in brain cell endoplasmic reticular (ER) membranes where they effect release of Ca2+ into the cytoplasm upon activation (opening) of the channel. They are redox sensors, possibly providing a partial explanation for how they control cytoplasmic Ca2+. Ry receptors have been identified in heart mitochondria where they provide the main pathway for Ca2+ entry. Sun et al. (2011) have demonstrated oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel (RyR1;TC# 1.A.3.1.2) by NADPH oxidase 4.

<span class="mw-page-title-main">Inositol polyphosphate kinase</span> Enzyme family

Inositol polyphosphate kinase (IPK) is a family of enzymes that have a similar 3-dimensional structure. All members of the family catalyze the transfer of phosphate groups from ATP to various inositol phosphates. Members of the family include inositol-polyphosphate multikinases, inositol-hexakisphosphate kinases, inositol-trisphosphate 3-kinases, and inositol-pentakisphosphate 2-kinase, which is more distantly related to the others

References

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