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 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. Human PDP1 and PDP2 were phosphorylated and activated by PKCδ upon insulin stimulation [2]. 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].

In addition to function as PD phosphatase, fruit fly PDP directly dephosphorylates Smad [6].

References

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