pseudokinase

The phrase pseudokinase was first coined in 2002.{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–34 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | bibcode = 2002Sci...298.1912M | s2cid = 26554314 }} They were subsequently sub-classified into different 'classes'.{{cite journal | vauthors = Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR | title = Emerging roles of pseudokinases | journal = Trends in Cell Biology | volume = 16 | issue = 9 | pages = 443–52 | date = September 2006 | pmid = 16879967 | doi = 10.1016/j.tcb.2006.07.003 }}{{cite journal | vauthors = Zeqiraj E, van Aalten DM | title = Pseudokinases-remnants of evolution or key allosteric regulators? | journal = Current Opinion in Structural Biology | volume = 20 | issue = 6 | pages = 772–81 | date = December 2010 | pmid = 21074407 | pmc = 3014569 | doi = 10.1016/j.sbi.2010.10.001 }}{{cite journal | vauthors = Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G | title = Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site | journal = Structure | volume = 17 | issue = 1 | pages = 128–38 | date = January 2009 | pmid = 19141289 | pmc = 2639636 | doi = 10.1016/j.str.2008.10.018 }}{{cite journal | vauthors = Eyers PA, Murphy JM | title = Dawn of the dead: protein pseudokinases signal new adventures in cell biology | journal = Biochemical Society Transactions | volume = 41 | issue = 4 | pages = 969–74 | date = August 2013 | pmid = 23863165 | doi = 10.1042/BST20130115 }} Several pseudokinase-containing families are found in the human kinome, including the Tribbles pseudokinases, which are at the interface between kinase and ubiquitin E3 ligase signalling.{{cite journal | vauthors = Eyers PA, Keeshan K, Kannan N | title = Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease | journal = Trends in Cell Biology | volume = 27 | issue = 4 | pages = 284–298 | date = April 2017 | pmid = 27908682 | pmc = 5382568 | doi = 10.1016/j.tcb.2016.11.002 }}{{cite journal | vauthors = Foulkes DM, Byrne DP, Yeung W, Shrestha S, Bailey FP, Ferries S, Eyers CE, Keeshan K, Wells C, Drewry DH, Zuercher WJ, Kannan N, Eyers PA | title = Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells. | journal = Science Signaling | volume = 11 | issue = 549 | date = September 2018 | pages = eaat7951 | pmid = 30254057 | doi = 10.1126/scisignal.aat7951 | pmc = 6553640 }}{{cite journal | vauthors = Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, Dunbier AK, Axtman AD, Kannan N, Mace PD | title = Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1 | journal = Science Signaling | volume = 11 | issue = 549 | date = September 2018 | pages = eaau0597 | pmid = 30254053 | doi = 10.1126/scisignal.aau0597| pmc = 6553639 }}

The human pseudokinases (and their pseudophosphatase cousins) are implicated in a wide variety of diseases,{{cite journal | vauthors = Reiterer V, Eyers PA, Farhan H | title = Day of the dead: pseudokinases and pseudophosphatases in physiology and disease | journal = Trends in Cell Biology | volume = 24 | issue = 9 | pages = 489–505 | date = September 2014 | pmid = 24818526 | doi = 10.1016/j.tcb.2014.03.008 }}{{cite journal | vauthors = Chen MJ, Dixon JE, Manning G | title = Genomics and evolution of protein phosphatases | journal = Science Signaling | volume = 10 | issue = 474 | pages = eaag1796 | date = April 2017 | pmid = 28400531 | doi = 10.1126/scisignal.aag1796 | s2cid = 41041971 }} which has made them potential drug targets and antitargets).{{cite journal | vauthors = Byrne DP, Foulkes DM, Eyers PA | title = Pseudokinases: update on their functions and evaluation as new drug targets | journal = Future Medicinal Chemistry | volume = 9 | issue = 2 | pages = 245–265 | date = January 2017 | pmid = 28097887 | doi = 10.4155/fmc-2016-0207 | doi-access = free }}{{cite journal | vauthors = Bailey FP, Byrne DP, McSkimming D, Kannan N, Eyers PA | title = Going for broke: targeting the human cancer pseudokinome | journal = The Biochemical Journal | volume = 465 | issue = 2 | pages = 195–211 | date = January 2015 | pmid = 25559089 | doi = 10.1042/BJ20141060 }}{{cite journal | vauthors = Cowan-Jacob SW, Jahnke W, Knapp S | title = Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases | journal = Future Medicinal Chemistry | volume = 6 | issue = 5 | pages = 541–61 | date = April 2014 | pmid = 24649957 | doi = 10.4155/fmc.13.216 }}{{cite journal | vauthors = Foulkes DM, Byrne DP, Bailey FP, Eyers PA | title = Tribbles pseudokinases: novel targets for chemical biology and drug discovery? | journal = Biochemical Society Transactions | volume = 43 | issue = 5 | pages = 1095–103 | date = October 2015 | pmid = 26517930 | doi = 10.1042/BST20150109 }} Pseudokinases are made up of an evolutionary mixture of eukaryotic protein kinase (ePK) and non ePK-related pseudoenzyme proteins (e.g., FAM20A, which binds ATP{{cite journal | vauthors = Cui J, Zhu Q, Zhang H, Cianfrocco MA, Leschziner AE, Dixon JE, Xiao J | title = Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding | journal = eLife | volume = 6 | date = April 2017 | pmid = 28432788 | pmc = 5413348 | doi = 10.7554/eLife.23990 | doi-access = free }} and is pseudokinase due to a conserved glutamate to glutamine swap in the alpha-C helix.{{cite journal | vauthors = Cui J, Xiao J, Tagliabracci VS, Wen J, Rahdar M, Dixon JE | title = A secretory kinase complex regulates extracellular protein phosphorylation | journal = eLife | volume = 4 | pages = e06120 | date = March 2015 | pmid = 25789606 | pmc = 4421793 | doi = 10.7554/eLife.06120 | doi-access = free }} FAM20A is implicated in periodontal disease, and serves to control the catalytic activity of FAM20C, an important physiological casein kinase that controls phosphorylation of proteins in the Golgi apparatus that are destined for secretion,{{cite journal | vauthors = Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Nguyen KB, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ, Dixon JE | title = A Single Kinase Generates the Majority of the Secreted Phosphoproteome | journal = Cell | volume = 161 | issue = 7 | pages = 1619–32 | date = June 2015 | pmid = 26091039 | pmc = 4963185 | doi = 10.1016/j.cell.2015.05.028 }} such as the milk protein casein.

A comprehensive evolutionary analysis confirms that pseudokinases group into multiple subfamilies, and these are found in the annotated kinome of organisms across the kingdoms of life, including prokaryotes, archaea and all eukaryotic lineages with an annotated proteome; this data is searchable in ProKino (http://vulcan.cs.uga.edu/prokino/about/browser).{{cite journal | vauthors = Kwon A, Scott S, Taujale R, Yeung W, Kochut KJ, Eyers PA, Kannan N | title = Tracing the origin and evolution of pseudokinases across the tree of life | journal = Science Signaling | volume = 12 | issue = 578 | date = April 2019 | pages = eaav3810 | pmid = 31015289 | doi = 10.1126/scisignal.aav3810 | pmc = 6997932 }} Some pseudokinases can still bind to ATP, or catalyse an atypical reaction involving migrated catalytic residues; moreover structural prediction algorithms such as AlphaFold can be used to analyse pseudokinase folding{{cite journal | vauthors = Shrestha S, Byrne DP, Harris JA, Kannan N, and Eyers PA | title = Cataloguing the dead: breathing new life into pseudokinase research. | journal = FEBS J | volume = 287 | issue = 19 | pages = 4150–4169 | date = Oct 2020 | pmid = 32053275 | pmc = 7586955 | doi = 10.1111/febs.15246 }} Some pseudokinases show species specific adaptions, including the vertebrate pseudokinase PSKH2, which like the closely-related secretory-pathway Ser/Thr kinase PSKH1 is a client of the HSP90 molecular chaperone system in human cells.{{cite journal | vauthors = Byrne DP, Shrestha S, Daly LA, Marensi V, Ramakrishnan K, Eyers CE, Kannan N, and Eyers PA | title = Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2 | journal = Biochemical Journal | volume = 480 | issue = 2 | pages = 141–160 | date = Jan 2023 | pmid = 39964718 | pmc = 11873932 | doi = 10.1042/BCJ20220474 }}

• Kinase
• Pseudoenzyme
• Phosphatome
• Protein phosphatase

{{Reflist|32em}}

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• {{cite journal | vauthors = Eyers PA, Murphy JM | title = The evolving world of pseudoenzymes: proteins, prejudice and zombies | journal = BMC Biology | volume = 14 | issue = 1 | pages = 98 | date = November 2016 | pmid = 27835992 | pmc = 5106787 | doi = 10.1186/s12915-016-0322-x | doi-access = free }}

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• {{cite web|url=https://www.liverpool.ac.uk/integrative-biology/staff/patrick-eyers/ |title=Professor Patrick Eyers - University of Liverpool Kinome Assay and Screening Facility |website=Liverpool.ac.uk |date= |accessdate=2017-01-16}}
• {{cite web|url=http://www.kinase.com |title=Kinome details and access to KinBase |accessdate=2017-01-16}}
• {{cite web|url=http://vulcan.cs.uga.edu/prokino/about/|title=Prokino software to analyse kinase site conservation = |accessdate=2017-01-16}}
• {{cite web|url=http://kinase.com/wiki/index.php/Pseudokinases |title=The human pseudokinome wiki |accessdate=2017-01-16}}

Category:Biochemistry

Category:Cell signaling

Category:Cancer