
A protein kinase is a
kinase
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 don ...
which selectively modifies other proteins by covalently adding
phosphate
Phosphates are the naturally occurring form of the element phosphorus.
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...
s to them (
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
) 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
The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...
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
Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
and
plants
Plants are the eukaryotes that form the kingdom Plantae; they are predominantly photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with cyanobacteria to produce sugars f ...
. 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
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
.
Chemical activity
The chemical activity of a protein kinase involves removing a phosphate group from
ATP and covalently attaching it to one of three
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s that have a free
hydroxyl group
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
. Most kinases act on both
serine
Serine
(symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
and
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...
, others act on
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
, and a number (
dual-specificity kinases) act on all three.
There are also protein kinases that phosphorylate other amino acids, including
histidine kinases that phosphorylate histidine residues.
Structure
Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core.
The structures of over 280 human protein kinases have been determined.
There are a number of conserved regions in the catalytic domain of protein kinases. In the
N-terminal extremity of the catalytic domain there is a
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
-rich stretch of residues in the vicinity of a
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
amino acid, which has been shown to be involved in ATP binding. In the central part of the catalytic domain, there is a conserved
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
, which is important for the catalytic activity of the enzyme.
Serine/threonine-specific protein kinases
Serine/threonine protein kinases () phosphorylate the OH group of
serine
Serine
(symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
or
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...
(which have similar side chains). Activity of these protein kinases can be regulated by specific events (e.g., DNA damage), as well as numerous chemical signals, including
cAMP/
cGMP,
diacylglycerol, and
Ca2+/
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
.
One very important group of protein kinases are the
MAP kinases (acronym from: "mitogen-activated protein kinases"). Important subgroups are the kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinases
JNK and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues. Activity of MAP kinases is restricted by a number of protein phosphatases, which remove the phosphate groups that are added to specific serine or threonine residues of the kinase and are required to maintain the kinase in an active conformation.
Tyrosine-specific protein kinases
Tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
-specific protein kinases ( and ) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
. They act primarily as
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
receptors and in downstream signaling from growth factors.
Some examples include:
*
Platelet-derived growth factor receptor (PDGFR)
*
Epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...
(EGFR)
*
Insulin receptor and
insulin-like growth factor 1 receptor (IGF1R)
*
Stem cell factor (SCF) receptor (also called ''c-kit'', see the article on
gastrointestinal stromal tumor).
Receptor tyrosine kinases
These kinases consist of extracellular domains, a transmembrane spanning
alpha helix
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...
, and an intracellular
tyrosine kinase domain protruding into the
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
. They play important roles in regulating
cell division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
,
cellular differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
, and
morphogenesis. More than 50 receptor tyrosine kinases are known in mammals.
Structure
The extracellular domains serve as the
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
-binding part of the molecule, often inducing the domains to form
homo- or
heterodimers. The transmembrane element is a single α helix. The intracellular or cytoplasmic
Protein kinase domain
The protein kinase domain is a structurally conserved sequence, conserved protein domain containing the catalytic function of protein kinases. Protein kinases are a group of enzymes that move a phosphate group onto proteins, in a process called ph ...
is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.
Regulation
Ligand binding causes two reactions:
#
Dimerization of two monomeric receptor kinases or stabilization of a loose dimer. Many ligands of receptor tyrosine kinases are
multivalent. Some tyrosine receptor kinases (e.g., the
platelet-derived growth factor
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing bloo ...
receptor) can form heterodimers with other similar but not identical kinases of the same subfamily, allowing a highly varied response to the extracellular signal.
# ''Trans''-autophosphorylation (phosphorylation by the other kinase in the dimer) of the kinase.
Autophosphorylation stabilizes the active conformation of the kinase domain. When several amino acids suitable for phosphorylation are present in the kinase domain (e.g., the insulin-like growth factor receptor), the activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation switches the kinase from "off" to "standby".
Signal transduction
The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the
ras protein signal-transduction chain.
Receptor-associated tyrosine kinases
Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in a number of signaling cascades, in particular those involved in
cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
signaling (but also others, including
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
). One such receptor-associated tyrosine kinase is
Janus kinase
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoverie ...
(JAK), many of whose effects are mediated by
STAT proteins. (''See
JAK-STAT pathway.'')
Dual-specificity protein kinases
Some kinases have
dual-specificity kinase activities. For example,
MEK (MAPKK), which is involved in the
MAP kinase cascade, is a both a serine/threonine and tyrosine kinase.
Histidine-specific protein kinases
Histidine kinases are structurally distinct from most other protein kinases and are found mostly in
prokaryote
A prokaryote (; less commonly spelled procaryote) is a unicellular organism, single-celled organism whose cell (biology), cell lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Gree ...
s as part of two-component signal transduction mechanisms. A phosphate group from ATP is first added to a histidine residue within the kinase, and later transferred to an
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...
residue on a 'receiver domain' on a different protein, or sometimes on the kinase itself. The aspartyl phosphate residue is then active in signaling.
Histidine kinases are found widely in prokaryotes, as well as in plants, fungi and eukaryotes. The
pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases, but instead phosphorylate serine residues, and probably do not use a phospho-histidine intermediate.
Aspartic acid/glutamic acid-specific protein kinases
Inhibitors
Deregulated kinase activity is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death. Drugs that inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec (
imatinib) and Iressa (
gefitinib
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targe ...
).
*
Anthra(1,9-cd)pyrazol-6(2H)-one
*
Staurosporine
Kinase assays and profiling
Drug developments for kinase inhibitors are started fro
kinase assays, the lead compounds are usually profiled for specificity before moving into further tests. Many profiling services are available from fluorescent-based assays t
an
competition binding assays
References
External links
Human and mouse protein kinases in UniProt: classification and indexKinase.Com Genomics, evolution and large-scale analysis of protein kinases (non-commercial).
KinMutBase: A registry of disease-causing mutations in protein kinase domains
KLIFS (Kinase-Ligand Interaction Fingerprints and Structures) Database -- analysis of kinase structures and kinase-inhibitor interactionsKinCore: the Kinase Conformation Resource: A web resource for protein kinase sequence, structure and phylogeny
{{DEFAULTSORT:Protein Kinase
EC 2.7
Protein kinases