Phosphatase Family PPP
Phosphatase Classification: Fold PPPL: Superfamily PPPL: Family PPP
PPPs are found in both eukaryotes and prokaryotes. PPPs share the highest sequence similarity compared to other phosphatase superfamilies. PPP are enzymatically active as part of a complex, consisting of one catalytic subunit and one or two regulatory subunits, of which there are a wide variety. Here, we focus on the catalytic subunit only.
Subfamilies
Note: PPP2C, PPP4C, PPP6C are grouped as PP2A in some literature.
PPP1C (PP1, catalytic subunit)
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, catalytic subunit)
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, catalytic subunit)
PPP4C, the catalytic subunit of Protein Phosphatase 4 (PP4) holoenzyme, is found widely in eukaryotes including animals, plants and fungi. Like other members in this family, PP4 has many different substrates and is involved in a wide variety of processes.
PPP6C (PP6, catalytic subunit)
PPP6C, the catalytic subunit of holoenzyme PP6, is found throughout eukaryotes.
PPP3C (PP2B/calcineurin, catalytic subunit)
PPP3C (PP2B, calcineurin) is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinical relevance. PPP3C (PP2B, calcineurin) is an attractive antifungal drug target.
PPP5C
PPP5C also known as Protein Phosphatase 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.
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 functions in sensory neurons
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, and some basal eukaryotes (Chromalveolata and Excavata), but not in plants or amoebazoa. It is found in some basal metazoans but absent from vertebrates, nematodes, and insects.
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.)
PPPLV subfamily
PPPLV stands for PPP lost in vertebrates.
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.
