Phosphatase Subfamily PPP1C

Phosphatase Classification: Fold PPPL: Superfamily PPPL: Family PPP: Subfamily PPP1C (catalytic subunit of PP1 holoenzyme)

PPP1C is a ubiquitous serine/threonine phosphatase found throughout eukaryotes and even in some prokaryotes. By forming complexes with different regulatory subunits, it is involved in many various processes.

Evolution

PPP1C subfamily is found throughout eukaryotes even in some prokaryotes. It has many lineage-specific gene duplications. In particular, 10 PPP1Cs are found in fruit fly, 3 in human, 3 in C. elegans, and 4 in yeast.

Domain

PPP1C has a single domain - phosphatase domain.

Functions

The PPP1C subfamily is the catalytic subunit of PP1 holoenzyme binding to regulatory subunits to achieve diverse functions [1, 2]. Over 50 different regulatory subunits are known in human and at least 20 in yeast. These different complexes play key roles in various cellular processes, such as cell cycle progression [3] and glycogen metabolism. Below are some examples:

PPP1C, in complex with regulatory subunits, dephosphorylates the substrates below:

• Myosin (light chain). PPP1C forms myosin-light-chain phosphatase (MLCP) in complex with PPP1R12A (MYPT1/M130) and PPP1R12B (M20).

• eIF2α. PPP1C-PPP1R15A (GADD34) holophosphatase in complex with G-actin, dephosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) and inhibits integrated stress response (ISR) [4, 5, 6].

• NIPP1. PPP1C, in complex with its regulatory subunit NIPP1, activates mesenchymal genes in HeLa cells, though its substrates in this biological process are unclear [7].

Regulatory subunits

PPP1R15B

A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature and microcephaly [8].

References

1. Heroes E, Lesage B, Görnemann J, Beullens M, Van Meervelt L, and Bollen M. The PP1 binding code: a molecular-lego strategy that governs specificity. FEBS J. 2013 Jan;280(2):584-95. DOI:10.1111/j.1742-4658.2012.08547.x |
2. Rebelo S, Santos M, Martins F, da Cruz e Silva EF, and da Cruz e Silva OA. Protein phosphatase 1 is a key player in nuclear events. Cell Signal. 2015 Dec;27(12):2589-98. DOI:10.1016/j.cellsig.2015.08.007 |
3. Grallert A, Boke E, Hagting A, Hodgson B, Connolly Y, Griffiths JR, Smith DL, Pines J, and Hagan IM. A PP1-PP2A phosphatase relay controls mitotic progression. Nature. 2015 Jan 1;517(7532):94-98. DOI:10.1038/nature14019 |
4. Chambers JE, Dalton LE, Clarke HJ, Malzer E, Dominicus CS, Patel V, Moorhead G, Ron D, and Marciniak SJ. Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. Elife. 2015 Mar 16;4. DOI:10.7554/eLife.04872 |
5. Rojas M, Vasconcelos G, and Dever TE. An eIF2α-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2α. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3466-75. DOI:10.1073/pnas.1501557112 |
6. Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, Shenolikar S, and Peti W. Structural and Functional Analysis of the GADD34:PP1 eIF2α Phosphatase. Cell Rep. 2015 Jun 30;11(12):1885-91. DOI:10.1016/j.celrep.2015.05.043 |
7. Van Dessel N, Boens S, Lesage B, Winkler C, Görnemann J, Van Eynde A, and Bollen M. Protein phosphatase PP1-NIPP1 activates mesenchymal genes in HeLa cells. FEBS Lett. 2015 May 22;589(12):1314-21. DOI:10.1016/j.febslet.2015.04.017 |
8. Abdulkarim B, Nicolino M, Igoillo-Esteve M, Daures M, Romero S, Philippi A, Senée V, Lopes M, Cunha DA, Harding HP, Derbois C, Bendelac N, Hattersley AT, Eizirik DL, Ron D, Cnop M, and Julier C. A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. Diabetes. 2015 Nov;64(11):3951-62. DOI:10.2337/db15-0477 |