Phosphatase Subamily Paladin

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Paladin: Subfamily Paladin

Evolution

Paladins are found in vertebrates and early metazoa such as sponge, trichoplax and nematostella but absent from arthropoda and nematoda. Paladins are also found in most plants and a small number of fungi (see internal database gOrtholog).

Domain

The Paladin subfamily has two phosphatase domains close to each in sequence. Both domains are homologous to cysteine phytases in bacteria whose crystal structures have a CC1 fold (so called "PTP-like") [1, 2, 3, 4]. Similar to protein phosphatases of CC1 fold such as PTPs and DSPs, these phytases are cysteine-based and have CX₅R motif. Both of phosphatase domains of paladin contain CX₅R motif. Based upon our current understanding of CC1 fold phosphatases, we predict paladin to be catalytically active.

Notes:

• The cysteine phytases is a class of phytases. The phytases remove phosphate from myo-inositol 1,2,3,4,5,6-hexakisphosphate. They have four distinct folds, including purple acid phosphatase in human.
• The homology between paladin and cysteine phytases were detected by HHpred and BLASTing against PDB database. The top hits of HHpred are cysteine phytases with identity around 20% followed by DSPs with slightly higher identity but lower coverage.

Function

Paladin has been very little studied. Human Paladin (PALD, PALD1) was found as an inhibitor of insulin signaling by knockdown and overexpression. Similar over and under-expression showed a role in neural crest cell formation and migration in chicken [5] and mutation of the two Cx5R cysteines did not affect this function.

Paladin's physiological substrate(s) is unclear. But, the bacterial cysteine phytases dephosphorylate myo-inositol 1,2,3,4,5,6-hexakisphosphate, but not pTyr [1].

References

1. Chu HM, Guo RT, Lin TW, Chou CC, Shr HL, Lai HL, Tang TY, Cheng KJ, Selinger BL, and Wang AH. Structures of Selenomonas ruminantium phytase in complex with persulfated phytate: DSP phytase fold and mechanism for sequential substrate hydrolysis. Structure. 2004 Nov;12(11):2015-24. DOI:10.1016/j.str.2004.08.010 |
2. Gruninger RJ, Dobing S, Smith AD, Bruder LM, Selinger LB, Wieden HJ, and Mosimann SC. Substrate binding in protein-tyrosine phosphatase-like inositol polyphosphatases. J Biol Chem. 2012 Mar 23;287(13):9722-9730. DOI:10.1074/jbc.M111.309872 |
3. Gruninger RJ, Thibault J, Capeness MJ, Till R, Mosimann SC, Sockett RE, Selinger BL, and Lovering AL. Structural and biochemical analysis of a unique phosphatase from Bdellovibrio bacteriovorus reveals its structural and functional relationship with the protein tyrosine phosphatase class of phytase. PLoS One. 2014;9(4):e94403. DOI:10.1371/journal.pone.0094403 |
4. Weber S, Stirnimann CU, Wieser M, Frey D, Meier R, Engelhardt S, Li X, Capitani G, Kammerer RA, and Hilbi H. A type IV translocated Legionella cysteine phytase counteracts intracellular growth restriction by phytate. J Biol Chem. 2014 Dec 5;289(49):34175-88. DOI:10.1074/jbc.M114.592568 |
5. Roffers-Agarwal J, Hutt KJ, and Gammill LS. Paladin is an antiphosphatase that regulates neural crest cell formation and migration. Dev Biol. 2012 Nov 15;371(2):180-90. DOI:10.1016/j.ydbio.2012.08.007 |
6. Huang SM, Hancock MK, Pitman JL, Orth AP, and Gekakis N. Negative regulators of insulin signaling revealed in a genome-wide functional screen. PLoS One. 2009 Sep 3;4(9):e6871. DOI:10.1371/journal.pone.0006871 |