Phosphatase Subfamily PPM1G

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

Evolution

PPM1G emerged in holozoa. Human has a single PPM1G (PP2CG/PP2Cγ/FIN13), as do most other organisms.

Domain

PPM1G consists almost entirely of a PPM fold phosphatase domain. The phosphatase domain has a highly acidic insert in which 75% of the 54 residues are glutamate or aspartate in human [1]. The acidic insert 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-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 the 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 that 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 [2, 8].

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].
• PPM1G is associated with alcohol use disorder [11].

PPM1Gs are found in Drosophila (CG10417) and C. elegans (F42G9.1), but neither are well characterized.

References

1. Travis SM and Welsh MJ. PP2C gamma: a human protein phosphatase with a unique acidic domain. FEBS Lett. 1997 Aug 4;412(3):415-9. DOI:10.1016/s0014-5793(97)00837-5 |
2. Allemand E, Hastings ML, Murray MV, Myers MP, and Krainer AR. Alternative splicing regulation by interaction of phosphatase PP2Cgamma with nucleic acid-binding protein YB-1. Nat Struct Mol Biol. 2007 Jul;14(7):630-8. DOI:10.1038/nsmb1257 |
3. Petri S, Grimmler M, Over S, Fischer U, and Gruss OJ. Dephosphorylation of survival motor neurons (SMN) by PPM1G/PP2Cgamma governs Cajal body localization and stability of the SMN complex. J Cell Biol. 2007 Nov 5;179(3):451-65. DOI:10.1083/jcb.200704163 |
4. Kimura H, Takizawa N, Allemand E, Hori T, Iborra FJ, Nozaki N, Muraki M, Hagiwara M, Krainer AR, Fukagawa T, and Okawa K. A novel histone exchange factor, protein phosphatase 2Cgamma, mediates the exchange and dephosphorylation of H2A-H2B. J Cell Biol. 2006 Nov 6;175(3):389-400. DOI:10.1083/jcb.200608001 |
5. Khoronenkova SV, Dianova II, Ternette N, Kessler BM, Parsons JL, and Dianov GL. ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 response to DNA damage. Mol Cell. 2012 Mar 30;45(6):801-13. DOI:10.1016/j.molcel.2012.01.021 |
6. Liu J, Stevens PD, Eshleman NE, and Gao T. Protein phosphatase PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1). J Biol Chem. 2013 Aug 9;288(32):23225-33. DOI:10.1074/jbc.M113.492371 |
7. Murray MV, Kobayashi R, and Krainer AR. The type 2C Ser/Thr phosphatase PP2Cgamma is a pre-mRNA splicing factor. Genes Dev. 1999 Jan 1;13(1):87-97. DOI:10.1101/gad.13.1.87 |
8. Suh EJ, Kim YJ, and Kim SH. Protein phosphatase 2Cgamma regulates the level of p21Cip1/WAF1 by Akt signaling. Biochem Biophys Res Commun. 2009 Aug 28;386(3):467-70. DOI:10.1016/j.bbrc.2009.06.056 |
9. Chaudhary N and Maddika S. WWP2-WWP1 ubiquitin ligase complex coordinated by PPM1G maintains the balance between cellular p73 and ΔNp73 levels. Mol Cell Biol. 2014 Oct 1;34(19):3754-64. DOI:10.1128/MCB.00101-14 |
10. Gudipaty SA, McNamara RP, Morton EL, and D'Orso I. PPM1G Binds 7SK RNA and Hexim1 To Block P-TEFb Assembly into the 7SK snRNP and Sustain Transcription Elongation. Mol Cell Biol. 2015 Nov;35(22):3810-28. DOI:10.1128/MCB.00226-15 |
11. Ruggeri B, Nymberg C, Vuoksimaa E, Lourdusamy A, Wong CP, Carvalho FM, Jia T, Cattrell A, Macare C, Banaschewski T, Barker GJ, Bokde AL, Bromberg U, Büchel C, Conrod PJ, Fauth-Bühler M, Flor H, Frouin V, Gallinat J, Garavan H, Gowland P, Heinz A, Ittermann B, Martinot JL, Nees F, Pausova Z, Paus T, Rietschel M, Robbins T, Smolka MN, Spanagel R, Bakalkin G, Mill J, Sommer WH, Rose RJ, Yan J, Aliev F, Dick D, Kaprio J, Desrivières S, Schumann G, and IMAGEN Consortium. Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis. Am J Psychiatry. 2015 Jun;172(6):543-52. DOI:10.1176/appi.ajp.2014.14030382 |