Kinase Group Atypical

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Kinase Classification: Atypical Group

The Atypical protein kinases (aPK) group is now split into several structural categories. All aPKs lack sequence similarity to the ePK domain HMM profile, but have been shown experimentally to have protein kinase activity or are clear homologs of other aPKs. All eukaryotic aPK families are small, several having just one member in vertebrates, and none in invertebrates. Other aPK families may remain to be discovered by biochemical methods, but since most atypical families are small, and most biochemically-discovered kinases are ePKs, it is unlikely that many new atypical kinases will be discovered. Conversely, some of these aPKs may be false positives, if the reports of kinase activity are not correct.

Structural homologs of ePKs

Several kinases previously defined as "Atypical" are now known to share the same PKL fold and catalytic mechanism as ePKs. These have been reclassified to a new group, called PKL.

Structural Homologs of other kinase enzymes

PDHK: Pyruvate Dehydrogenase Kinases

This family of mitochondrial kinases contains a domain which is similar to prokaryotic histidine kinases, but has been shown biochemically to phosphorylate serine rather than histidine. Crystal structures confirm that the PDHK domain fold is similar to that of histidine kinases, distinct from the ePK domain [1, 2].

NDK: Nucleoside diphosphate Kinases

This universal group is known to phosphorylate NDPs to make NTPs, using a phospho-histidine intermediate, but has also been reported to have protein kinase activity in mammals, Drosophila and ciliates.

PyK: Pyruvate Kinase

Human Pyruvate Kinase M2 (PKM2) phosphorylates ADP in a key step of glycolysis. Recent findings indicate that PKM2 also has protein tyrosine kinase activity, and possibly histidine kinase activity that is tied to cell proliferation regulation in cancer. No other form of pyruvate kinase has been implicated as a protein kinase.

SAPPK: Structurally Atypical Putative Protein Kinases

Several proteins have reported protein kinase biochemical activity but are not members of any known kinase fold or have a known mechanism of phosphotransfer. Most have only one or a few papers supporting their kinase activity. Since some proteins (see below) are now thought to be non-kinases, despite initial supporting evidence, it may be that many of these proteins are not bona fide kinases, but can bind tightly to other kinases and so show activity. Many are known to autophosphorylate but not transphosphorylate, suggesting that if they are kinases, they have a limited substrate range.


  1. Machius M, Chuang JL, Wynn RM, Tomchick DR, and Chuang DT. Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11218-23. DOI:10.1073/pnas.201220098 | PubMed ID:11562470 | HubMed [Machius]
  2. Steussy CN, Popov KM, Bowker-Kinley MM, Sloan RB Jr, Harris RA, and Hamilton JA. Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a serine protein kinase. J Biol Chem. 2001 Oct 5;276(40):37443-50. DOI:10.1074/jbc.M104285200 | PubMed ID:11483605 | HubMed [Steussy]
All Medline abstracts: PubMed | HubMed