2017년 3월 17일 금요일

Protein kinase

Protein kinase

Protein kinase (Protein kinase; protein kinase) is the enzyme which adds phosphate group to protein molecules (phosphorylates). I call it the protein kinase in protein kinase or Anglicism. I call kinase phosphorylating protein in kinase (transphosphorylase) protein kinase, but often call this protein kinase kinase in particular (it is said with merely kinase with this article afterward).

The conception diagram which protein kinase gets phosphate group from ATP, and phosphorylates protein.

Table of contents

Summary

The cell phosphorylates intracellular protein to maintain the function and repeats a reaction to dephosphorylate. The protein changes an enzyme activity, local existence in the cell and meeting state with other protein by this phosphorylation. The intracellular protein of 30% catches the change by the kinase and functions as an adjustment factor of various signal transmission and metabolism in the cell. The kinase gene has approximately 500 kinds in human genome and occupies all eukaryotic genetic approximately 2% again.

The kinase moves phosphate group of the ATP to a hydroxy group in the amino acid residue and has activity to let you covalently link. The kinase lets you phosphorylate serine, threonine, a tyrosine residue mainly among amino acids, but more than 99% of amino acids which kinase phosphorylates are serine, threonine (serine / threonine kinase). However, there are many cases that phosphorylation (tyrosine kinase) of tyrosine less than 0.1% is more important biologically. A thing in response to all these three kinds, in addition, react to an imidazole ring nitrogen atom of histidine with a microbe and the plant, and there is (included in histidine kinase, EC 2.7.13) again, too. The activity of the kinase is regulated precisely, and the kinase receives ON/OFF adjustment by phosphorylation, too. This may be performed by oneself as well as other kinase and says "autophosphorylation". These adjustment is caused by the bond of other activated (or they restrain it) protein and small molecule compounds, the localized change in the cell.

The dysfunction of the kinase often becomes an ill cause. A detailed study is conducted about a cancer in particular, and the kinase participates in adjustment of an increase, movement, permeation and the apoptosis (cell death) of the cancer cell. The drug which can help treatment by inhibiting specific kinase is developed, and there is the thing which has been already used clinically like Gefitinib (Iressa ®) and imatinib (グリベック ®) among them.

Serine / threonine kinase

Serine / threonine kinase (Ser/Thr kinase; reading: serine / threonine kinase, EC 2.7.11.*) phosphorylates a hydroxy group of serine or threonine. These

It is regulated によって. Because the phosphorylated substrate is connected with kinase with a key and several amino acids (by a hydrophobic bond and the ionic bonding) that it is not the thing based on the specific amino acid sequence as for the specificity of these kinase, kinase is usually specific for the "substrate family" whole sharing the property that there is. Most kinase binds to the kinase like a true substrate, but it is inhibited by "a para-substrate" lacking in an amino acid catching the phosphorylation. When a para-substrate is removed, the kinase regains a function. The catalytic part of these kinase is saved highly. There was not the original EC number and used "EC 2.7.1.37" for serine / threonine kinase except a part before. I reviewed it, and it was done by naming Committee of association of international biochemistry molecular biology IUBMB (NC-IUBMB), and an individual EC number was assigned in 2005.

Phosphorylase kinase

Phosphorylase kinase (EC 2.7.11.19) is the serine / threonine kinase which was discovered for the first time (in 1959 Edo Vin crepe and others). I activate glycogen phosphorylase (the enzyme which phosphorolysis makes glycogen).

Protein kinase A

As for protein kinase A (A kinase or PKA, EC 2.7.11.11), as for the small domain, the large domain has alpha helix in beta sheet from two domains. The gap of two domains includes the binding site of a substrate and the ATP. When a substrate is combined with ATP, two domains move to turn each other, and it is in the position where the target amino acid of the end phosphate group and substrate of the ATP approaches it, and a reaction is easy to get up.

Control

The A kinase catches the adjustment with the cAMP in a cell and has glycogen, sugar, some functions including the adjustment of the adipose metabolism. When there is not cAMP, from a tetramer (two regulatory subunits and two catalytic subunits: R2C2), a regulatory subunit blockades the active center of the catalytic subunit. When cAMP binds to the regulatory subunit, I dissociate it into two RC, and this has activity. In addition, catalytic subunit in itself is regulated by phosphorylation, too. As for the A kinase, it is done down regulation by the following feedback system: One of the substrates activated by A kinase has phosphodiesterase, and this converts cAMP into AMP and I lower the quantity of cAMP and reduce activity of the A kinase. A kinase phosphorylates phosphorylase kinase and, in the resolution of the glycogen, is activated and this phosphorylates glycogen phosphorylase more and is activated.

Protein kinase C

Summary

 
Schematic view of the PKC activation mechanism

Protein kinase C (the protein kinase sea) or PKC, the C kinase (EC 2.7.11.13) are protein families comprised of isozyme more than at least ten kinds. The PKC phosphorylates the hydroxyl group of serine which there is to a substrate and the threonine residue. I was discovered in 1977 by Yasutomi Nishizuka and others. The PKC is classified in three subfamilies of the existing-type (conventional or classical: α, βI, βII, γ) new (novel: δ, ε, η, θ) unrepresentativeness (atypical: ζ, λ/ι) by the structure, activated mechanism, physiology. The existing-type PKC is activated mainly by phosphatide such as a calcium ion (Ca2+), diacylglycerol (DAG, DG) or the phosphatidylserine (PS). The new PKC loses calcium ion binding activity and receives activation with the diacylglycerol. Because it is produced from phosphatidylinositol (PI) where diacylglycerol is a cell membrane, a component of the nuclear membrane by phospholipase C, the new PKC is located in the down stream of the phospholipase C a usual type in a signal transmission course. On the other hand, the unrepresentativeness PKC does not have Cal SIMM ion and diacylglycerol binding activity. I may call Cα which is one kind of the existing-type PKC C kinase in particular in Japan.

Isozymic

Structure and control

The existing-type PKC consists of the adjustment domain of the N-terminal side and the catalytic domains of the C-terminal side. I shift to cytoplasm and usually phosphorylate substrates when there is the PKC to cytoplasm with inactivated state for the self-inhibition action by the pseudosubstrate domain existing in the adjustment domain, and I am activated by a second messenger (calcium and diacylglycerol). There are two consecutive C1 domains (a diacylglycerol-binding domain: C1A and C1B) and C2 domains (calcium ion-binding domain) in the adjustment domain of the existing-type PKC. The new PKC has two consecutive C1 domains like a usual type, but C2 domain of the existing-type PKC and the C2 like domain having a homology do not connect a calcium ion. The unrepresentativeness PKC has only one C1 domain, but the direed Al glycerol binding activity is lost. All PKC isozymic catalytic domain consists of ATP-binding domain and kinase domains.

I show the primary structure which is common to existing-type PKC as an example:

H2N – Pseudosubstrate domain – C1A - C1B - C2 domain – ATP-binding domain (C3) – Kinase domain (C4) - COOH

Function

The target sequence of the PKC is similar to a thing of the A kinase, and there is a basic amino acid near serine / threonine residue catching the phosphorylation. There are MARCKS (Myristoylated alanine-rich C kinase substrate) protein, MAP kinase, IκB which is transcription factor inhibition protein, vitamin D3 receptor (VDR), Raf kinase, calpain and epidermal growth factor receptor (EGFR) to a substrate, and it is thought that I carry a particularly central role in the signal transmission in the cell. In addition, I am known as a main target of the bryostatin that a clinical trial is carried out as carcinogenetic promoters such as 12-O- tetradecanoylphorbol 13 - acetate (TPA) and an anticancer agent. It is revealed that the PKC participates in various diseases including a cancer and Alzheimer's disease.

Ca2+/ calmodulin-dependent protein kinase

EC 2.7.11.17. I am called the calmodulin (CaM) kinase, and it is activated mainly by Ca2+/ calmodulin complex. There is the property that an activation state lasts long even if "memory action" that is an activated reaction is over about activation. With two types of the next:

  • Specific model calmodulin kinase: An example includes myosin light chain kinase (MLCK). I let this phosphorylates myosin, and muscle shrink.
  • Multifunctional model calmodulin kinase: I am called calmodulin kinase II and work in the secretion of the neurotransmitter, the control of the transcription factor, various scenes including the glycogen metabolism. 1-2% of the protein of the brain are calmodulin kinase II.

I autoregulate it with structure and it

The calmodulin kinase consists of the catalytic domain of the N-terminal side, an adjustment domain and accompaniment domains. When there is not Ca2+/ calmodulin, the catalytic domain receives the self-control by the adjustment domain (including the sequence similar to the substrate). Some molecules associate, and the calmodulin kinase becomes homooligomer or the hetero oligomer. The calmodulin kinase molecules phosphorylate it each other when activated by Ca2+/ calmodulin. Two are effective against this:

  1. The affinity to a calmodulin complex increases, and sustained time of the kinase activity extends
  2. After a calmodulin complex dissociated, activation lasts, and more sustained time extends

MAP kinase

 
Kinase cascade sketch
The details refer to "division promotion factor activator protein kinase"

Abbreviation of Mitogen-activated protein kinases (mitogen activation protein kinase, division promotion factor activator protein kinase, EC 2.7.11.24). Because I was activated when I handled a cell with mitogen (generic name of the cell proliferation promoter), there was this name. MAPKKKK => MAPKKK => MAPKK => I form a cascade called MAPK (with the kind that this is general notation, and K means kinase each, but is really various) and am activated sequentially and I finally phosphorylate a transcription factor and control a cell cycle and an increase.

Mos/Raf kinase

Raf is activated by small molecule type GTP-binding protein or C kinase including Ras (oncogene product) of GTP-binding (active form) and I phosphorylate downstream MEK kinase and am activated. Mos specifically develops by the reduction division of the animal egg, and the activity (including downstream MEK-MAPK-p90Rsk) is done with requisiteness for a division stop (the invertebrates such as starfishs stop for G1 period just after the reduction division) by meiotic progress and a subtracter second division. These kinase in itself was identified as an original oncogene (c-mos, c-raf) product originally, too.

cdc2

As a control factor of the interphases of the cell cycles, division yeast, a frog, a starfish were discovered in some eukaryotes independently. (the study that became targeted for receiving a prize of Nobel Prize for Medicine of 2001.) The way of the control varies according to a creature, but all have activity by protein called cyclin and a thing and itself connected being phosphorylated and control the characteristic phenomenon (including the formation of nuclear membrane collapse, chromosome cohesion, the spindle-shaped cube) of the interphase by phosphorylating a specific substrate.

Tyrosine kinase

The tyrosine kinase (or protein tyrosine kinase, Protein Tyrosine Kinase; PTK, EC 2.7.10.*) is the enzyme which specifically phosphorylates a tyrosine residue of the protein. There is it only to a multicellular organism and participates in signal transmission about differentiation, increase, adhesion of the cell or immunoreaction. It is classified roughly in the type 2 of the non-receptor type which a growth factor does not couple with a reception figure to be activated by a growth factor being connected. When tyrosine kinase is activated, I specifically phosphorylate protein to assume receptor oneself or a target. Various signal transmission factors recognizing this phosphorylation site by autophosphorylation of receptor oneself bind to the receptor, and signal transmission begins. In addition, by phosphorylation of the target protein, intracellular various protein is activated in sequence, and signal transmission begins. By a cancer and expectation Roma characteristics arteriosclerosis, the psoriasis, I may be activated excessively.

[1] expected that there is the tyrosine kinase of the Homo sapiens more than 100 kinds, most of do not know a function.

Reception figure tyrosine kinase

It is the structure that 膜貫 makes a cell membrane and has the binding site of the growth factor outside a cell and has a tyrosine kinase active site in the cytoplasm domain. EC 2.7.10.1。 50 kinds or more are known to the growth factor for the mammal, and the reception figure tyrosine kinase converts the stimulation of this growth factor into the signal in the cell and plays an important role by division, differentiation, the morphosis of the cell. I nominate below a representative thing.

Structure

The reception figure tyrosine kinase consists of three domains. It is the domain in the cell with the domain where a growth factor binds to out of the cell, 疎水性膜貫領域 penetrating a cell membrane, tyrosine kinase activity. Furthermore, the domain in the cell is distributed between three of a juxtamembrane domain, a kinase activity domain, the C-terminal domain. Like an insulin acceptor and an insulin-like growth factor, a domain out of the cell independently separates it, and there is the thing taking the structure to bind to the receptor body by disulfide combination. 膜貫領域 consists of single alpha helix.

When a growth factor binds to the receptor in the domain out of the cell, the receptor is activated and moves over a cell membrane and I am connected to other receptors and form a dimer. Different receptors can connect that the same receptors are connected (homodimer) (heterodimer).

Control

Two reactions are caused by the combination of the growth factor:

  1. The dimerization of two receptors molecules or loose dimeric stabilization. As for the ligand which assumes tyrosine kinase a receptor, most can connect "multivalent" (polyvalence characteristics) that is 1 molecule to plural receptors molecules. Some tyrosine kinase including platelet-derived growth factor receptor (PDGFR) makes different similar kinase and heterodimer, and they can lead various replies to cell outside signal.
  2. I autophosphorylate a transformer (one dimeric phosphorylating another): Two subdomains of the kinase take the placement that ATP does not accept in the active center with the inactivated form. The position of the subdomain changes by autophosphorylation and ATP enters and becomes able to react.

When there are some amino acids catching the phosphorylation with a kinase domain, the kinase activity rises so that there are many phosphorylated amino acids. In this case the first phosphorylation is called cis autophosphorylation, and the kinase is replaced by a "standby" state from "off" in this.

Non-reception figure tyrosine kinase

The representative structure binds to the cell membrane in a cell without having a domain out of the cell and is structure to have a tyrosine kinase part on the intracellular end side. With binding sites such as immunoglobulin or cytokine, I am activated by these stimulation.

  • Oncogene product c-Src
  • Jak： Make an activated receptor and complex; because phosphorylate a receptor without being rich, and phosphorylate the down stream molecules which bound to the receptor next, is called "Janus kinase" (Janus kinase) for both sides God Janus. Jak phosphorylates STAT (signal transducers and activators of transcription) and STAT which I phosphorylated forms a dimer and activates a shift, transcription in a nucleus. This signal transduction system is called Jak-STAT system.

Histidine kinase

The histidine-specific kinase (EC 2.7.13.x) is classified in the GHKL type kinase/ATPase superfamily unlike other kinase structurally. The histidine kinase is seen in fungi and a plant other than a prokaryote and functions by "2 ingredients system signal transmission". At first the phosphate group of the ATP is moved to the histidine residue (imidazole ring nitrogen atom) of kinase molecules and is moved to the aspartic acid residue in "a receiver domain" of other protein (in the case of the same kinase molecules, there is it) afterwards (the energy of the ATP is not necessary for this stage). When delivery of such a phosphoric acid is repeated more, there is it. As a result, transcription control is performed. Phosphorylation aspartic acid transmits a signal as an active form. A plant hormone (cytokinin, ethylene) receptor or a photoreceptor are known for the various receptors, plants sensing a state (osmotic pressure, oxygen or nutrition) out of the cell with the microbe.

Pyruvate dehydrogenase kinase in the animals is GHKL type kinase resembling histidine kinase structurally, but phosphorylates a serine residue of the pyruvic acid dehydrogenase directly without transmitting 2 ingredients system signal through histidine.

Aspartic acid / glutaminic acid kinase

EC 2.7.12.x

Footnote

  1. ^ Plowman GD, Sudarsanam S, Bingham J, et al. "Review. The protein kinases of Caenorhabditis elegans: It is 13,603-13,610 a model for signal transduction in multicellular organisms." Proceedings of the National Academy of Sciences of the United States of America 1999, 96. PMID 10570119

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