| Structural highlights
4xpn is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | PPP1CA, PPP1A (HUMAN), PPP1R15A, GADD34 (HUMAN) |
| Activity: | Phosphoprotein phosphatase, with EC number 3.1.3.16 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[PP1A_HUMAN] Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development.[1] [PR15A_HUMAN] Recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'.[2] [3] [4] [5] [6]
Publication Abstract from PubMed
The attenuation of protein synthesis via the phosphorylation of eIF2alpha is a major stress response of all eukaryotic cells. The growth-arrest- and DNA-damage-induced transcript 34 (GADD34) bound to the serine/threonine protein phosphatase 1 (PP1) is the necessary eIF2alpha phosphatase complex that returns mammalian cells to normal protein synthesis following stress. The molecular basis by which GADD34 recruits PP1 and its substrate eIF2alpha are not fully understood, hindering our understanding of the remarkable selectivity of the GADD34:PP1 phosphatase for eIF2alpha. Here, we report detailed structural and functional analyses of the GADD34:PP1 holoenzyme and its recruitment of eIF2alpha. The data highlight independent interactions of PP1 and eIF2alpha with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells. This work greatly enhances our molecular understanding of a major cellular eIF2alpha phosphatase and establishes the foundation for future translational work.
Structural and Functional Analysis of the GADD34:PP1 eIF2alpha Phosphatase.,Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, Shenolikar S, Peti W Cell Rep. 2015 Jun 30;11(12):1885-91. doi: 10.1016/j.celrep.2015.05.043. Epub, 2015 Jun 18. PMID:26095357[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mi J, Guo C, Brautigan DL, Larner JM. Protein phosphatase-1alpha regulates centrosome splitting through Nek2. Cancer Res. 2007 Feb 1;67(3):1082-9. PMID:17283141 doi:10.1158/0008-5472.CAN-06-3071
- ↑ Connor JH, Weiser DC, Li S, Hallenbeck JM, Shenolikar S. Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1. Mol Cell Biol. 2001 Oct;21(20):6841-50. PMID:11564868 doi:http://dx.doi.org/10.1128/MCB.21.20.6841-6850.2001
- ↑ Brush MH, Weiser DC, Shenolikar S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol. 2003 Feb;23(4):1292-303. PMID:12556489
- ↑ Yagi A, Hasegawa Y, Xiao H, Haneda M, Kojima E, Nishikimi A, Hasegawa T, Shimokata K, Isobe K. GADD34 induces p53 phosphorylation and p21/WAF1 transcription. J Cell Biochem. 2003 Dec 15;90(6):1242-9. PMID:14635196 doi:http://dx.doi.org/10.1002/jcb.10711
- ↑ Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol. 2004 Jan 19;164(2):291-300. Epub 2004 Jan 12. PMID:14718519 doi:10.1083/jcb.200307151
- ↑ Zhan Q, Lord KA, Alamo I Jr, Hollander MC, Carrier F, Ron D, Kohn KW, Hoffman B, Liebermann DA, Fornace AJ Jr. The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth. Mol Cell Biol. 1994 Apr;14(4):2361-71. PMID:8139541
- ↑ Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, Shenolikar S, Peti W. Structural and Functional Analysis of the GADD34:PP1 eIF2alpha Phosphatase. Cell Rep. 2015 Jun 30;11(12):1885-91. doi: 10.1016/j.celrep.2015.05.043. Epub, 2015 Jun 18. PMID:26095357 doi:http://dx.doi.org/10.1016/j.celrep.2015.05.043
|
