Phosphatase Subfamily PDPc
Phosphatase Classification: Fold PPM: Superfamily PPM: Family PPM: Subfamily PDPc
Evolution of pyruvate dehydrogenase (PD) phosphatase, PD kinase (PDK) and PD complex (PDC)
The PDPc subfamily is found in most eukaryotes (see internal database, though it's regulatory subunit, PDPR, is mostly found in eumetazoa (see internal database. The opposing Pyruvate Dehydrogenase Kinase family is found in almost all eukaryotes. The substrate human PD complex has two subunits: alpha (PDHA1 or PDHA2), and beta (PDHB). Both subunits are found almost all eukaryotes.
Domain
PDPc has single structural domain, the phosphatase domain. It is thought to have a mitochondria targeting sequence (MTS), but no conserved MTS is found by computational prediction using MitoProt.
Functions
The subfamily encodes the catalytic subunit of pyruvate dehydrogenase phosphatase complex, which is a heterodimer consisting of catalytic and regulatory subunits. Its substrate, the pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The PDC is regulated by Pyruvate Dehydrogenase Kinases and PDPs through inhibitory serine phosphorylation. Because of its critical role in regulating PDC, it is not surprising that PDP1 deficiency may cause severe clinical course. Null mutation caused a lethal infantile phenotype [1].
The subfamily is conserved in its mitochondria localization and phosphatase activity towards PD, as shown in both vertebrates [2] and yeast [3].
The two human phosphatases of PDP subfamily PDP1 and PDP2 are widely expressed in different tissues according to the RNA-seq data from GTEx. Human PDP1 are expressed at a higher level than PDP2 (see here for PDP1 and here for PDP2). PDP1 is slightly more abundant in ardrenal gland, some parts of brain, heart, and testis than other tissues.
Human PDPs are regulated by tyrosine phosphorylation. There are multiple tyrosine positions can be phosphorylated, such as Tyr-94 [4], Tyr-381 [5], Tyr-79, Tyr-46. The phosphorylation at different positions can lead to different effects on PD complex phosphorylation state [4, 5]. Human PDP1 and PDP2 were phosphorylated and activated by PKCδ upon insulin stimulation [2].
In addition to function as PD phosphatase, fruit fly PDP directly dephosphorylates Smad [6].
References
- Cameron JM, Maj M, Levandovskiy V, Barnett CP, Blaser S, Mackay N, Raiman J, Feigenbaum A, Schulze A, and Robinson BH. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. Hum Genet. 2009 Apr;125(3):319-26. DOI:10.1007/s00439-009-0629-6 |
- Caruso M, Maitan MA, Bifulco G, Miele C, Vigliotta G, Oriente F, Formisano P, and Beguinot F. Activation and mitochondrial translocation of protein kinase Cdelta are necessary for insulin stimulation of pyruvate dehydrogenase complex activity in muscle and liver cells. J Biol Chem. 2001 Nov 30;276(48):45088-97. DOI:10.1074/jbc.M105451200 |
- Krause-Buchholz U, Gey U, Wünschmann J, Becker S, and Rödel G. YIL042c and YOR090c encode the kinase and phosphatase of the Saccharomyces cerevisiae pyruvate dehydrogenase complex. FEBS Lett. 2006 May 15;580(11):2553-60. DOI:10.1016/j.febslet.2006.04.002 |
- Shan C, Kang HB, Elf S, Xie J, Gu TL, Aguiar M, Lonning S, Hitosugi T, Chung TW, Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, and Fan J. Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J Biol Chem. 2014 Aug 1;289(31):21413-22. DOI:10.1074/jbc.M114.581124 |
- Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, Gu TL, Aguiar M, Lonning S, Chen H, Mohammadi M, Britton LM, Garcia BA, Alečković M, Kang Y, Kaluz S, Devi N, Van Meir EG, Hitosugi T, Seo JH, Lonial S, Gaddh M, Arellano M, Khoury HJ, Khuri FR, Boggon TJ, Kang S, and Chen J. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell. 2014 Feb 20;53(4):534-48. DOI:10.1016/j.molcel.2013.12.026 |
- Chen HB, Shen J, Ip YT, and Xu L. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev. 2006 Mar 15;20(6):648-53. DOI:10.1101/gad.1384706 |
