Kinase Subfamily PI4K2

Kinase Classification: Group PKL: Family PIK: Subfamily PI4K2

PI4K2 are phosphatidyl inositol 4' kinases. They are members of the PKL fold of protein kinases and appear to be highly distant members of the PIK family of phosphatidyl inositol 3' and 4' kinases.

Evolution

PI4K2 are found in almost all eukaryotes, and in several clades of bacteria. There are two human members, PI4K2A and PI4K2B.

Catalytic Activity

Despite the name, plant members of this family from wheat and Arabidopsis have shown protein autophosphorylation activity, but not lipid kinase activity [1, 2]. Yeast and mammalian forms are known to have lipid kinase activity.

Sequence Notes

The catalytic loop is uncertain, as PI4K2 have two adjacent DxxxxN motifs close to where the catalytic loop can be, and neither ones gives a uniquely good alignment to other PKL kinases. The first of these motifs has a consensus of NTDRgndN. The fourth position R is also absolutely conserved in PI3K and PI4K1, and the DN residues are also mostly conserved in PI3K, suggesting that this may be the correct activation loop. Mutation of the putative D166 and N171 residues of this first motif in rat PI4K2 resulted in complete or almost complete loss of activity [3], but both motifs are conserved even in bacteria, suggesting that both D and both N residues are critical for function.

Apart from this similarity, PI4K2 have no obvious remote sequence similarity to the other PIK subfamilies beyond its similarity to the PKL fold (and their common substrates). Some remote searches suggest that GASK kinases are weakly related to PI4K2, and that the remote actin-fragmin kinase (AFK) structure from Physarum polycephalum may also be related. A published alignment of actin-fragmin kinase with PI4K2 and other kinases does support that the second DxxxxN motif is the catalytic loop, and shows the first DxxxxN to be present in AFK [4]. There is as yet no published structure for a PI4K2.

References

1. Liu P, Xu ZS, Pan-Pan L, Hu D, Chen M, Li LC, and Ma YZ. A wheat PI4K gene whose product possesses threonine autophophorylation activity confers tolerance to drought and salt in Arabidopsis. J Exp Bot. 2013 Jul;64(10):2915-27. DOI:10.1093/jxb/ert133 |
2. Galvão RM, Kota U, Soderblom EJ, Goshe MB, and Boss WF. Characterization of a new family of protein kinases from Arabidopsis containing phosphoinositide 3/4-kinase and ubiquitin-like domains. Biochem J. 2008 Jan 1;409(1):117-27. DOI:10.1042/BJ20070959 |
3. Barylko B, Wlodarski P, Binns DD, Gerber SH, Earnest S, Sudhof TC, Grichine N, and Albanesi JP. Analysis of the catalytic domain of phosphatidylinositol 4-kinase type II. J Biol Chem. 2002 Nov 15;277(46):44366-75. DOI:10.1074/jbc.M203241200 |
4. Steinbacher S, Hof P, Eichinger L, Schleicher M, Gettemans J, Vandekerckhove J, Huber R, and Benz J. The crystal structure of the Physarum polycephalum actin-fragmin kinase: an atypical protein kinase with a specialized substrate-binding domain. EMBO J. 1999 Jun 1;18(11):2923-9. DOI:10.1093/emboj/18.11.2923 |