Pseudokinase
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Pseudokinases are catalytically-deficient
pseudoenzyme Pseudoenzymes are variants of enzymes that are catalytically-deficient (usually inactive), meaning that they perform little or no enzyme catalysis. They are believed to be represented in all major enzyme families in the kingdoms of life, where t ...
variants of
protein kinases 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 fun ...
that are represented in all
kinome In molecular biology, biochemistry and cell signaling the kinome of an organism is the complete set of protein kinases encoded in its genome. Kinases are usually enzymes that catalyze phosphorylation reactions (of amino acids) and fall into severa ...
s across the kingdoms of life. Pseudokinases have both physiological (
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 ...
) and
pathophysiological Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...
functions.


History

The phrase pseudokinase was first coined in 2002. They were subsequently sub-classified into different 'classes'. Several pseudokinase-containing families are found in the human
kinome In molecular biology, biochemistry and cell signaling the kinome of an organism is the complete set of protein kinases encoded in its genome. Kinases are usually enzymes that catalyze phosphorylation reactions (of amino acids) and fall into severa ...
, including the Tribbles pseudokinases, which are at the interface between kinase and ubiquitin E3 ligase signalling. The human pseudokinases (and their pseudophosphatase cousins) are implicated in a wide variety of diseases, which has made them potential
drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
s and antitargets). Pseudokinases are made up of an evolutionary mixture of eukaryotic protein kinase (ePK) and non ePK-related
pseudoenzyme Pseudoenzymes are variants of enzymes that are catalytically-deficient (usually inactive), meaning that they perform little or no enzyme catalysis. They are believed to be represented in all major enzyme families in the kingdoms of life, where t ...
proteins (e.g.,
FAM20A Pseudokinase FAM20A is a protein that in humans is encoded by the ''FAM20A'' gene. Function FAM20A belongs to an evolutionarily conserved family of secreted proteins expressed in many tissues. This locus encodes a protein that is likely sec ...
, which binds ATP and is pseudokinase due to a conserved
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
to
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
swap in the alpha-C helix. FAM20A is implicated in
periodontal disease Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main c ...
, and serves to control the catalytic activity of
FAM20C Family with sequence similarity 20, member C also known as FAM20C or DMP4 is a protein which in humans is encoded by the ''FAM20C'' gene. Fam20C, a Golgi localized protein kinase, is a serine kinase that phosphorylates both casein and other highl ...
, an important physiological casein kinase that controls
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 ...
of proteins in the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
that are destined for secretion, such as the milk protein
casein Casein ( , from Latin ''caseus'' "cheese") is a family of related phosphoproteins (CSN1S1, αS1, aS2, CSN2, β, K-casein, κ) that are commonly found in mammalian milk, comprising about 80% of the proteins in cow's milk and between 20% and 60% of ...
. A comprehensive evolutionary analysis confirms that pseudokinases group into multiple subfamilies, and these are found in the annotated
kinome In molecular biology, biochemistry and cell signaling the kinome of an organism is the complete set of protein kinases encoded in its genome. Kinases are usually enzymes that catalyze phosphorylation reactions (of amino acids) and fall into severa ...
of organisms across the kingdoms of life, including prokaryotes, archaea and all eukaryotic lineages with an annotated
proteome A proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. P ...
; this data is searchable in ProKino (http://vulcan.cs.uga.edu/prokino/about/browser). Some pseudokinases can still bind to ATP, or catalyse an atypical reaction involving migrated catalytic residues; moreover structural prediction algorithms such as
AlphaFold AlphaFold is an artificial intelligence (AI) program developed by DeepMind, a subsidiary of Alphabet, which performs predictions of protein structure. It is designed using deep learning techniques. AlphaFold 1 (2018) placed first in the overall ...
can be used to analyse pseudokinase folding Some pseudokinases show species specific adaptions, including the vertebrate pseudokinase PSKH2, which like the closely-related secretory-pathway Ser/Thr kinase
PSKH1 Protein Serine/threonine-protein kinase H1 is a Ser/Thr protein kinase that is encoded by the ''PSKH1'' gene in humans and is associated with organelle membranes. PSKH1 resides within, and transits between, organelles in the human secretory pathw ...
is a client of the
HSP90 Hsp90 (heat shock protein 90) is a chaperone (protein), chaperone protein that assists other proteins to protein folding, fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of ...
molecular chaperone system in human cells.


See also

*
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 ...
*
Pseudoenzyme Pseudoenzymes are variants of enzymes that are catalytically-deficient (usually inactive), meaning that they perform little or no enzyme catalysis. They are believed to be represented in all major enzyme families in the kingdoms of life, where t ...
*
Phosphatome The phosphatome of an organism is the set of phosphatase genes in its genome. Phosphatases are enzymes that catalyze the removal of phosphate from biomolecules. Over half of all cellular proteins are modified by phosphorylation which typically con ...
*
Protein phosphatase A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its Substrate (biochemistry), substrate protein. Protein phosphorylation is one of the most common forms of reversible protei ...


References


Further reading

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External links

* * * * {{cite web, url=http://kinase.com/wiki/index.php/Pseudokinases , title=The human pseudokinome wiki , accessdate=2017-01-16 Biochemistry Cell signaling Cancer