Kinase Group PKL

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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 that includes most protein kinases. Many of these were previously classified as "Atypical".

ABC1/ADCK/UbiB: ABC1 domain containing kinase

This 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.

PIKK: Phosphatidyl inositol 3’ kinase-related kinases

These proteins are most similar to the PIK family of phospatidyl inositol kinases, but instead have protein kinase activity, implicated in DNA repair (ATM, ATR, DNAPK), nonsense-mediated decay (SMG) and nutrient stress signaling (mTOR).

PIK: Phosphatidyl Inositol Kinases

Related to PIKK, these phosphorylate phosphatidyl inositol on the 3' and 4' positions (PI3K, PI4K), and some have autokinase activity.

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 [3]. 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.

AGPHD1

Phosphorylates 5-hydroxy-lysine kinase during catabolism of collagen. Subfamily of CAK kinases, with a single human gene, AGPHD1.

PIPK

Phosphatidyl Inositol Phosphate Kinases, some of which have shown protein kinase activity.

Other PKL families

Some of the most remote human kinases of the "Other" group of ePKs can be considered as PKL families in their own right [4], but have been left within the 'Other' group for consistency. These include 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 [4].


Non-protein kinases in the PKL fold

Several other kinases have a PKL fold but are not known to have protein kinase activity. There are listed here to be structurally complete and because other 'non-protein' kinases have been shown to have cryptic protein kinase activity.

ITPK

An inositol kinase (Inositol 1, 3, 4-trisphosphate 5/6-kinase). This is annotated as having an ATP-grasp fold rather than a PKL fold, but given its similarity to PIPK (and ATP-grasp/PKL intermediate) and conservation of catalytic residues with PKL, we include it in the PKL fold for comparisons. Once reported to have protein kinase activity, it is now thought not to have.

IPPK

IPPK phosphorylates the 2 position of an inositol already phosphorylated on all other positions, to make IP6 - inositol hexakisphosphate, a signaling molecule.

IPK

A set of 3 subfamilies that further phosphorylate inositol phosphates, and have structures intermediate between PKL and ATP-Grasp folds.

FN3K

Fructosamine Kinase, which phosphorylates glycated residues of old proteins, as a first step in their deglycosylation and rejuvenation. FN3K are related to the CAK family.

CAK

A family expanded in bacteria, which includes human choline and ethanolamine kinase, AGPHD1, and KACAD, as well as aminoglycoside resistance kinases (APH).

References

  1. 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. PubMed ID:9799791 | HubMed [Leonard]
  2. 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. PubMed ID:11389851 | HubMed [Yamaguchi]
  3. 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. PubMed ID:11972772 | HubMed [Angermayr]
  4. 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 | PubMed ID:17355172 | HubMed [Kannan]
All Medline abstracts: PubMed | HubMed