Difference between revisions of "Phosphatase Subfamily PPM1G"

Revision as of 17:24, 22 September 2015

Phosphatase Classification: Fold PPM (PP2C): Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1G

Evolution

PPM1G emerged in holozoa, usually single copy per genome. Human has a single PPM1G (PP2CG/PP2Cγ/FIN13).

Domain

The PPM1G subfamily has a single structural domain, the phosphatase domain of PPM fold. Unlike any other known phosphatase, PPM1G has a highly acidic domain (AD): 75% of the 54 residues are glutamate or aspartate [1]. The acidic domain is essential for its activity in splicing and interacts with YB-1, a splicesome-associated factor [2].

Human PPM1G also has a N-terminal myristoylation site and a predicted C-terminal nuclear localization signaling [3].

Functions

PPM1G is a nuclear phosphatase [3]. Northern blot analysis shows that human PPM1G is widely expressed, and is most abundant in testis, skeletal muscle, and heart [1]. RNA-seq data from GTEx also shows its broad expression in different tissues and particularly abundant in testis. Its best known function is involved in splicesome (see below). Like other PPMs (PP2Cs), recombinant PPM1G requires Mg2+ or Mn2+ for activity [1]. Human PPM1G has the substrates below:

• Nucleosome-free Histones H2A-H2B. Alternatively, the phosphatase activity and/or substrate specificity of PPM1G might be controlled by binding with histones [4].

• Deubiquitylation enzyme USP7/HAUSP. PPM1G dephosphorylates USP7S which leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53 [5].

• 4E binding protein 1 (4E-BP1). PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1), which binds to translation initiation factor 4E and inhibits cap-dependent translation in a phosphorylation-dependent manner [6].

• Survival motor neurons (SMN) complex. PPM1G interacts with and dephosphorylates SMN complex, possibly the components SMN and Gemin3. The dephosphorylation reduces the stability of the SMN complex and its level in nuclear Cajal bodies [3].

• Splicesome. PPM1G is a splicing factor modulates alternative splicing of specific pre-mRNAs coregulated by YB-1, a splicesome-associated factor [2]. It dephosphorylates specific substrates required for the formation of the spliceosome [7], but the substrates are unclear [8]. [2].

PPM1G may have other functions and/or be involved in other processes:

• PPM1G inactivates monomeric the E3 ligase WWP2 and promotes the assembly of two E3 ligases WWP2-WWP1 heterodimeric complex [9]. It is unclear whether PPM1G dephosphorylates WWP1 or WWP2.
• PPM1G binds to 7SK RNA and the kinase inhibitor Hexim1 once P-TEFb kinase has been released from the 7SK small nuclear ribonucleoprotein (7SK snRNP) complex. The P-TEFb kinase phosphorylates RNA Polymerase II (Pol II) after the release from 7SK nRNP complex, therefore regulating transcription elongation [10].

Besides, PPM1G is associated with alcohol use disorder [11].

References

1. Error fetching PMID 9276438: [Travis97]
2. Error fetching PMID 17572683: [Allemand07]
3. Error fetching PMID 17984321: [Petri07]
4. Error fetching PMID 17074886: [Kimura06]
5. Error fetching PMID 22361354: [Khoronenkova12]
6. Error fetching PMID 23814053: [Liu13]
7. Error fetching PMID 9887102: [Murray99]
8. Error fetching PMID 19538940: [Suh09]
9. Error fetching PMID 25071155: [Chaudhary14]
10. Error fetching PMID 26324325: [Gudipaty15]
11. Error fetching PMID 25982659: [Ruggeri15]