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A protein kinase is an enzyme that can transfer a phosphate group from a donor molecule (usually ATP) to an amino acid residue of a protein. The protein kinase mechanism is used in signal transduction for the regulation of enzymes: phosphorylation can activate (or inhibit) the activity of an enzyme. Although most protein kinases are specialized for a single kind of amino acid residue, some exhibit dual kinase activity (they can phosphorylate two different kinds of amino acid).
Protein kinases can be regulated by:
.
Serine/threonine protein kinases (EC 2.7.1.37) phosphorylate the OH group of serine or threonine (which have similar sidechains). These protein kinases can be regulated by:
These kinases are not specific to a similar consensus sequence (a consensus sequence is a group of flanking amino acids that determines whether the protein kinase can act on it). Since the substrate to be phosphorylated aligns with the kinase by several key amino acids (usually through hydrophopic forces and ionic bonds), a kinase is usually specific, not to a single substrate, but to a whole "substrate family" having common properties. Most kinases are inhibited by a pseudosubstrate that binds to the kinase like a real substrate but lacks the amino acid to be phosphorylated. When the pseudosubstrate is removed, the kinase can perform its normal function.
The catalytic domain of these kinases is highly conserved.
Many serine/threonine protein kinases do not have their own individual EC numbers and use "2.7.1.37", which is a general EC number for any enzyme that phosphorylates proteins while converting ATP to ADP (i.e. ATP:protein phosphotransferases.) This category is currently being reviewed by the Nomenclature Committee of IUBMB (NC-IUBMB), and it is believed that the various serine/threonine-kinases will get their own EC numbers eventually.
Phosphorylase kinase (EC 2.7.1.38) was the first Ser/Thr protein kinase to be discovered (in 1959 by Krebs et al.).
Main article cAMP-dependent protein kinase
Protein kinase A (EC 2.7.1.37) consists of two domains, a small domain with several β sheet structures and a larger domain containing several α helices. The binding sites for substrate and ATP are located in the catalytic cleft between the domains (or lobes). When ATP and substrate bind, the two lobes rotate so that the terminal phosphate group of the ATP and the target amino acid of the substrate move into the correct positions for the catalytic reaction to take place.
Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It is controlled by cAMP: in the absence of cAMP, the kinase is a tetramer of two regulatory and two catalytic subunits (R2C2), with the regulatory subunits blocking the catalytic center of the catalytic subunits. Binding of cAMP to the regulatory subunit leads to dissociation of active RC dimers. Also, the catalytic subunit itself can be regulated by phosphorylation.
Downregulation of protein kinase A occurs by a feedback mechanism: one of the substrates that is activated by the kinase is a phosphodiestrase, which converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A.
Protein kinase C (EC 2.7.1.37) is actually a family of protein kinases that require Ca2+, diacylglycerol, and a phospholipid such as phosphatidylcholine for activation. Thus, protein kinase C is activated through the same signal transduction pathway as phospholipase C. At least twelve members of the proteine kinase C family have been identified in mammals, due to their high sequence homology. The protein kinase C usually means the protein kinase Cα enzyme.
Protein kinase C enzymes consist of an N-terminal regulatory domain and a C-terminal catalytic domain. The kinases are inactive in the absence of activating agents, due to autoinhibition of the regulatory domain. They can be activated tumor promotors such as plasma membrane by phospholipase; fatty acids may also play a role in long-term activation.
The consensus sequence of protein kinase C enzymes is similar to that of protein kinase A, since it contains basic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are MARCKS proteins, MAP kinase, transcription factor inhibitor IκB, the vitamin D3 receptor VDR, Raf kinase, calpain, and the EGF receptor.
Also called CaM kinases(EC 2.7.1.123), these kinases are primarily regulated by the Ca2+/calmodulin complex. These kinases show a memory effect on activation. Two types of CaM kinases are:
The CaM kinases consist of an N-terminal catalytic domain, a regulatory domain, and an associative domain. In the absence of Ca2+/calmodulin, the catalytic domain is autoinhibited by the regulatory domain, which contains a pseudosubstrate sequence. Several CaM kinases aggregate into a homooligomer or heterooligomer. Upon activation by Ca2+/calmodulin, the activated CaM kinases autophosphorylate each other in an intermolecular reaction. This has two effects:
Mitogen-activated protein kinases (EC 2.7.1.37).
Main article: Tyrosine kinase
Tyrosine-specific protein kinases(EC 2.7.1.112) are, like serine/threonine-specific kinases, used in signal transduction. They act primarily as growth factor receptors; some examples:
These kinases consist of a transmembrane receptor with a tyrosine kinase domain protruding into the cytoplasm. They play an important role in regulating cell division, cellular differentiation, and morphogenesis. More than 50 known receptor tyrosine kinases are known in mammals.
The extracellular domain serves as the ligand receptor. It can be a separate unit that is attached to the rest of the receptor by a disulfide bond. The same mechanism can be used to bind two receptors together to form a homo- or heterodimer. The transmembrane element is a single α helix. The intracellular or cytoplasmic domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions.
Ligand binding causes two reactions:
The autophosphorylation causes the two subdomains of the intrinsic kinase to shift, opening the kinase domain for ATP binding. In the inactive form, the kinase subdomains are aligned so that ATP cannot reach the catalytic center of the kinase. 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 is said to be a cis-autophosphorylation, switching the kinase from "off" to "standby".
The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the ras protein signal-transduction chain.
Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes 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 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 and fungi. 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.
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