Pseudokinase

Pseudokinases are catalytically-deficient (usually inactive) pseudoenzyme variants of protein kinases that are broadly defined at the bioinformatic level, and are represented in all kinomes that have been compiled across the kingdoms of life. Analysis of pseudokinases has been achieved through the varied interdisciplinary efforts of bioinformaticians, structural biologists, biochemists and cell biologists, and is becoming increasingly important, especially as their highly diverse biological functions are being revealed, and the complexity of intracellular signalling by both kinase-dependent and independent mechanisms has become apparent. Their important regulatory and often disease-associated functions in signalling pathways are also shedding new light on the non-catalytic functions of active (canonical) protein kinases, and are suggesting new ways to target and interpret cellular signalling mechanisms using small molecule kinase modulators, especially since some, but not all, pseudokinases demonstrate experimental retention of nucleotide-binding and/or weak vestigial catalytic activity in vitro.

Pseudokinases were first discussed in depth (and named) in 2002. They were subsequently sub-classified into different 'classes' based upon experimental studies and research resource reviews. Several important pseudokinase-containing families are found in the human kinome, including the Tribbles pseudokinases, which have evolved interesting pseudo-lives at the interface between kinase and Ubiquitin E3 ligase signalling. The human pseudokinases (and their numerous pseudophosphatase cousins) are implicated in a wide variety of diseases, which has made them very interesting contemporary drug targets (and indeed potential antitargets).. Pseudokinases are made up of an evolutionary mixture of eukaryotic protein kinase (ePK) and non ePK-related pseudoenzyme proteins; a prominent example of the latter is the pseudokinase FAM20A, which binds ATP in a highly unusual conformation and is pseudokinase due to a conserved Glutamate to Glutamine swap in the alpha-C helix . FAM20A is implicated in periodontal disease, and serves to control the catalytic activity of FAM20C, the critically important physiological casein kinase that controls phosphorylation of proteins in the Golgi that are destined for secretion , such as the milk protein casein.

After an increase in activity during 2008 and 2009, the new pseudokinase field began to gather real traction at a Biochemical Society 'Hot-topic' event in late 2010. Contemporary 'cell signaling' meetings are increasingly recognising the importance of pseudokinases in prokaryotic and eukaryotic biology, and several pseudokinase-orientated meetings have occurred since the pseudokinase 'field' coalesced between 2008 and 2010. The world's first pseudoenzyme-badged meeting in 2016 also had a strong focus on pseudokinases, and the fourth international kinase and pseudokinase-focused meeting will take place in December 2018 in San Diego.

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