Phosphatase Subfamily PPIP5K
Phosphatase Classification: Fold HP: Superfamily HP (histidine phosphatase): Family HP, branch 2: PPIP5K
PPIP5K has a pseudophosphatase domain which bind to PtdIns(3,4,5)P3 and a kinase domain of RimK superfamily. The proteins therefore show kinase activity which convert InsP6 and 5-InsP7 to 1-InsP7 and InsP8.
Evolution
PPIP5K is conserved broadly in eukaryotes, including animals, fungi and plants. Most vertebrates have at least two copies. Non-vertebrate metazoan and fungi usually have one copy per genome.
Domain
PPIP5K has two domains: N-terminal RimK/ATP-grasp domain, and C-terminal HP2 domain [1]. The same domain combination is also found in plants.
RimK/ATP-grasp domain confer PPIP5K's kinase activity that converts InsP6 and 5-InsP7 to 1-InsP7 and InsP8 [1, 2].
Unlike other members of HP2 family which are protein or non-protein phosphatases, the HP2 domain of PPIP5K is not catalytically active. Instead, this HP2 domain is specialized for binding PtdIns(3,4,5)P3, as a partial PH (pleckstrin homology) consensus sequence is spliced into this HP2 domain [3].
Catalytic activity and functions
As mentioned above, the phosphatase domain of PPIP5K, HP2 domain, is catalytically inactive [3]. Because the kinase domain is active, the proteins show kinase activity in general. In particular, human PPIP5K1 and PPIP5K2 mediates phosphorylation of InsP6 and 5-InsP7 to 1-InsP7 and InsP8. InsP7 and InsP8 are multifunctional signaling molecules that regulate diverse cellular activities [1, 2].
References
- Fridy PC, Otto JC, Dollins DE, and York JD. Cloning and characterization of two human VIP1-like inositol hexakisphosphate and diphosphoinositol pentakisphosphate kinases. J Biol Chem. 2007 Oct 19;282(42):30754-62. DOI:10.1074/jbc.M704656200 |
- Choi JH, Williams J, Cho J, Falck JR, and Shears SB. Purification, sequencing, and molecular identification of a mammalian PP-InsP5 kinase that is activated when cells are exposed to hyperosmotic stress. J Biol Chem. 2007 Oct 19;282(42):30763-75. DOI:10.1074/jbc.M704655200 |
- Gokhale NA, Zaremba A, Janoshazi AK, Weaver JD, and Shears SB. PPIP5K1 modulates ligand competition between diphosphoinositol polyphosphates and PtdIns(3,4,5)P3 for polyphosphoinositide-binding domains. Biochem J. 2013 Aug 1;453(3):413-26. DOI:10.1042/BJ20121528 |
