Kinase Group PKL
Kinase Classification: PKL Group
The PKL group of kinases consists of several diverse kinase families that have the PKL fold and catalytic mechanism, but do not have further refinements of the ePKs, the class of kinases that includes most protein kinases. Many of these were previously classified as "Atypical".
ABC1/ADCK/UbiB: ABC1 domain containing kinase
This conserved family was identified as putative kinases by sequence alignment methods (Psi-Blast and HMMs) which show a domain that is weakly similar to the ePK domain, with particular conservation of the most conserved catalytic motifs. Their kinase similarity was first published by Leonard et al [1]. Despite the lack of overall sequence conservation with the ePK domain, these kinases contain candidates for the most conserved kinase motifs, including the VAIK catalytic motif (VAVK, VAMK), the DFG motif, and a QTD motif that may take the place of the HRD motif.
Alpha Kinases
The progenitors of this family are the myosin heavy chain kinases (MHCKs) of Dictyostelium discoideum and the eukaryotic elongation factor 2 kinase (eEF2K) found in most eukaryotes. Several other mammalian genes have been found to be homologous to these, including the channel kinases Chak1 and Chak2, which are multi-pass transmembrane proteins which act as kinases and as ion channels. Crystal structure of the CHAK1 gene [2] shows a PKL fold, and catalytic activity has been demonstrated for many members of this family.
This family contains a phosphatidyl inositol 3,4, kinase domain (PIK or PI3K), flanked by an N-terminal FAT domain and a C-terminal FATC domain [3]. Five of the six human members of this family have experimentally verified protein kinase activity and probably do not function as phosphatidyl inositol kinases. Multiple sequence alignment shows that the PIK domains of PIKKs form a distinct domain subfamily from both PI3K and PI4K, and solved structures show that it adopts a PKL fold, with conservation of the main catalytic residues, including the 'catalytic' K, the DFG motif and the HRD motif (modified to DRH) (see for instance [4]).
RIO
This family has 3 clear subfamilies, with one member of each in fly, worm and human. Yeast has two members (in the RIO1 and RIO2 subfamilies) and the fungus Aspergillus nidulans has a member of the third subfamily, RIO3. Homologs are also present in several archeal genomes. Yeast RIO1 was shown to have serine kinase activity [5]. The sequences do not align with the eukaryotic protein kinase domain, but many of the catalytic residues are strongly conserved in the RIO family, and overall structural similarity to ePKs has been predicted [1].
Golgi-Associated Kinase (GASK)
These kinases are found in the Golgi and are secreted, and known to phosphorylate proteins and sugar residues on proteoglycans. They are weakly related to PI4K kinases.
Other PKL families
Some of the most remote human kinases of the "Other" group of ePKs now have risen to the status of distinct PKL families, including Bub1, Scyl, Bud32 and Haspin (HRK). Many other PKL families are mostly bacterial, though some such as FruK and CAK also have some eukaryotic members. For more on these PKL classes, see Kannan et al, 2007 (PLoS Biology) [6].
References
- Leonard CJ, Aravind L, and Koonin EV. Novel families of putative protein kinases in bacteria and archaea: evolution of the "eukaryotic" protein kinase superfamily. Genome Res. 1998 Oct;8(10):1038-47. DOI:10.1101/gr.8.10.1038 |
- Yamaguchi H, Matsushita M, Nairn AC, and Kuriyan J. Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell. 2001 May;7(5):1047-57. DOI:10.1016/s1097-2765(01)00256-8 |
- Bosotti R, Isacchi A, and Sonnhammer EL. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci. 2000 May;25(5):225-7. DOI:10.1016/s0968-0004(00)01563-2 |
- Walker EH, Perisic O, Ried C, Stephens L, and Williams RL. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature. 1999 Nov 18;402(6759):313-20. DOI:10.1038/46319 |
- Angermayr M, Roidl A, and Bandlow W. Yeast Rio1p is the founding member of a novel subfamily of protein serine kinases involved in the control of cell cycle progression. Mol Microbiol. 2002 Apr;44(2):309-24. DOI:10.1046/j.1365-2958.2002.02881.x |
- Kannan N, Taylor SS, Zhai Y, Venter JC, and Manning G. Structural and functional diversity of the microbial kinome. PLoS Biol. 2007 Mar;5(3):e17. DOI:10.1371/journal.pbio.0050017 |
