Phosphatase Family PPPc

Phosphatase Classification: Fold MTDP: Superfamily MTDP: Family PPP

PPP can be found in both eukaryotes and prokaryotes. PPPs share the highest sequence similarity compared to other phosphatase superfamilies. PPP carries out phosphatase activity through complex (aka holoenzyme) rather than in monoenzyme. The PPP holoenzyme consists of one catalytic subunit and one or two regulatory subunits. Here, we focus on the catalytic subunit only. (PS: PPP has a large number of regulatory subunits. Perhaps, it is better to study and document their evolution and function by complex.)

Subfamilies

PPP1C (PP1)

PPP1C, catalytic subunit of holoenzyme PP1, is a ubiquitous serine/threonine phosphatase found throughout eukaryotes and even in some prokaryotes. Holoenzyme PP1 is involved in many various processes.

PPP2C (PP2A)

PPP2C, catalytic subunit of holoenzyme PP2A, is found throughout eukaryotes with various number in different lineages. PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process.

PPP4C (PP4)

PPP4C, catalytic subunit of Protein Phosphatase 4 (PP4) holoenzyme, is closely related to PPP2C, PP2A catalytic subunit. Similar to PP2A, the catalytic subunit can form heterodimers and heterotrimers with regulatory subunits. At least 6 have been found. Both of PP4 and PP2A dephoshorylate the phophorylated histone 2A variant, γ-H2AX, a marker for DNA damage and cell-cycle arrest, but they participate different physiological processes. While PP2A function after DNA damage, PP4 dephosphorylates γ-H2AX during S phase.

PPP6C (PP6) subfamily

PPP6C, catalytic subunit of Protein Phosphatase 6 (PP6) holoenzyme, is closely related to PPP2C, PP2A catalytic subunit. Similar to PP2A and PP4, PP6 also dephoshorylates the phophorylated histone 2A variant, γ-H2AX, a marker for DNA damage and cell-cycle arrest. In addition, PP6 also regulates mitotic spindle formation by controlling the T-loop phosphorylation state of the kinase Aurora A bound to its activator TPX2.

PPP3C (PP2B, calcineurin) subfamily

PPP3C is a calcium-dependent phosphatase, which binds to regulatory subunit to form heterodimer complex, known as calcineurin (CN) or Protein Phosphatase 2B (PP2B).

It is conserved from yeast to human, and it participates in very various cellular processes, from cell cycle progression to cardiac hypertrophy (see review PMID: 11015619). In particular, it activates the T cells of the immune system in mammals. When an antigen-preseting cell interacts with a T cell receptor on T cells, the cytoplasmic level of calcium increases, which activates calcineurin. Calcineurin activates a vertebrate-specific transcription factor called NFATc. It is used as a target for several immunosuppressive drugs. This phosphatase has clinical significance for schizophrenia and diabetes.

PPP5C subfamily

PPP5C also known as Protein Phospahtase 5 (PP5) is unique among PPP family members in that its catalytic and regulatory domains are contained in the same polypeptide chain. It has a tetratricopeptide repeat (TPR) domain which maintains the phosphatase in an auto-inhibited conformation that is neutralized when the heat shock protein Hsp90, or fatty acids, bind to this region. ε.

The phosphatase interacts with various proteins and participate in multiple signaling pathways. The phosphatase interacts with ATM, ATR, 53BP1, and DNA-depdent protein kianse catalytic subunits (DNA-PKc) following DNA damage. While enchance the activity of ATM and ATR, the phosphatase negatively regulates 53BP1 and DNA-PKc by dephosphorylating them. It regulates Raf-MEK-ERK pathway via inhibiting Raf-1 by dephosphorylating Serine 338. PPP5 is involved in mammalian circadian clock by activating the major clock kinae casein kinase I (CKI) ε. In addition, the elevated levels of this phosphatase may be associated with breast cancer development.

PPP7C (PPEF) subfamily

PPEFs contain calmodulin-binding motif IQ and calcium-binding domains EF hand to the N- and C-terminal side of phosphatase domain, respectively, which suggests its involvement in calcium signaling. This would be a reminiscent of another PPP subfamily, PPP3C (calcineurin/PP2B), which are regulated by calmodulin and another EF-hand protein, calcineurin B.

In C. elegans, Drosophila and mammals, PPEF expression was mainly detected in various sensory neurons. The Drosophila PPEF phosphatase, rdgC, is essential for dephosphorylation of rhodopsin. However, mice lacking both PPEF1 and PPEF2 showed no signs of photoreceptor synases. PPEF is present not only in animals but unicellular eukaryotes, indicating its ancient origin and basic functions of eukaryotes. The function and evolution of this phosphatase is reviewed in paper PMID: 19662497.

YNL217W (yeast) subfamily

Function unknown. It is found in most fungi, some basal metazoans but absent from almost all of deuterostomia, some basal eukaryotes (Chromalveolata and Excavata), but not found in plants or amoebazoan. (Note: the evolutionary history is from gOrtholog.)

PPG1 (yeast) subfamily

The gene PPG encodes a novel yeast protein phosphatase involved in glycogen accumulation (see SGD database). It is found in all fungi, and absent from holozoan. It is not found in plants, but is found in Dictyostellium and some basal eukaryotes. (Note: the evolutionary history is from gOrtholog.)

Nematode-specific PPP subfamilies

At least 36 PPPs are only found in C. elegans. Taking account the total number of PPPs in most eukaryotes is less than 20, this expansion is very unusual. However, almost nothing is known about these phosphatases.