Abstract
Protein phosphatase 1 (PP1) is a dinuclear metalloenzyme that catalyzes the dephosphorylation of serine and threonine residues. In this work, the catalytic reaction mechanism of PP1 was theoretically investigated by hybrid density functional theory. Firstly, an initial model of the Mn(II)–Mn(II) active site of PP1 was constructed on the basis of the high-resolution crystal structure, and stationary points along the reaction pathway were optimized and analyzed. The calculations provide strong support for the mechanism of the dephosphorylation by PP1 and suggest that His125 plays the role of donating a proton to the leaving group. Furthermore, reaction models with the Mn–Mn centers at different oxidation states [Mn(III)–Mn(II) and Mn(III)–Mn(III) centers] were designed. Our calculations show that increasing the oxidation state of one or both Mn(II) can shorten the bond lengths between the metal ions and the ligands, and increase the energy barrier of the related reactions. We found it interesting that artificially adding a negatively charged hydroxy ligand into the Mn(III)–Mn(II) center can recover the shortened coordination bonds and lower the increased energy barrier. Our investigation suggests that the definite oxidation states of the metal centers should be significantly correlated to the negative charges of the ligands not only in phosphoprotein phosphatases, but also in purple acid phosphatases and Escherichia coli 5′-nucleotidase. This means that all the members of phosphoprotein phosphatases adopt homodivalent centers, and suggests the heterovalent active sites of purple acid phosphatases have evolved from homodivalent ones.
Similar content being viewed by others
References
Ceulemans H, Bollen M (2004) Physiol Rev 84:1–39
Barford D (1995) Curr Opin Struct Biol 5:728–734
Gallego M, Virshup D (2005) Curr Opin Cell Biol 17:197–202
Kelker M, Page R, Peti W (2009) J Mol Biol 385:11–21
Maynes J, Luu H, Cherney M, Andersen R, Williams D, Holmes C, James M (2006) J Mol Biol 356:111–120
Maynes J, Bateman K, Cherney M, Das A, Luu H, Holmes C, James M (2001) J Biol Chem 276:44078–44082
Griffith J, Kim J, Kim E, Sintchak M, Thomson J, Fitzgibbon M, Fleming M, Caron P, Hsiao K, Navia M (1995) Cell 82:507–522
Xing Y, Xu Y, Chen Y, Jeffrey P, Chao Y, Lin Z, Li Z, Strack S, Stock J, Shi Y (2006) Cell 127:341–353
Shi Y (2009) Cell 139:468–484
Klabunde T, Sträter N, Fröhlich R, Witzel H, Krebs B (1996) J Mol Biol 259:737–748
Knöfel T, Sträter N (2001) J Mol Biol 309:239–254
Sträter N (2006) Purinerg Signal 2:343–350
Mitic N, Noble C, Gahan L, Hanson G, Schenk G (2009) J Am Chem Soc 131:8173–8179
Egloff M, Cohen P, Reinemer P, Barford D (1995) J Mol Biol 254:942–959
Goldberg J, Huang H, Kwon Y, Greengard P, Nairn A, Kuriyan J (1995) Nature 376:745–753
Mitic N, Smith SJ, Neves A, Guddat LW, Gahan LR, Schenk G (2006) Chem Rev 106:3338–3363
Liao RZ, Ding WJ, Yu JG, Fang WH, Liu RZ (2008) J Comput Chem 29:1919–1929
Liao RZ, Yu JG, Raushel FM, Himo F (2008) Chem Eur J 14:4287–4292
Liao RZ, Yu JG, Himo F (2009) Inorg Chem 48:1442–1448
Yang L, Liao RZ, Yu JG, Liu RZ (2009) J Phys Chem B 113:6505–6510
Liao RZ, Yu JG, Himo F (2010) J Phys Chem B 114:2533–2540
Ma Y, Sun Q, Zhang H, Peng L, Yu JG, Smith SC (2010) J Phys Chem B 114:9698–9705
Ma Y, Sun Q, Li Z, Yu JG, Smith SC (2012) J Phys Chem B 116:1426–1436
Liu YF, Liao RZ, Ding WJ, Yu JG, Liu RZ (2011) J Biol Inorg Chem 16:745–752
Lee C, Yang W, Parr RG (1988) Phys Rev B 37:785–789
Becke AD (1993) J Chem. Phys 98:5648–5652
Becke AD (1993) J Chem Phys 98:1372
Frisch MJ et al (2009) Gaussian 09, revision A.02. Gaussian, Wallingford
Zhurko G, Zhurko D (2005) ChemCraft, Lite version build
Siegbahn PEM (2000) Inorg Chem 39:2923–2935
Siegbahn PEM (2001) Theor Chem Acc 105:197–206
Schenk G, Boutchard CL, Carrington LE, Noble CJ, Moubaraki B, Murray KS, De Jersey J, Hanson GR, Hamilton S (2001) J Biol Chem 276:19084–19088
Merkx M, Pinkse MWH, Averill BA (1999) Biochemistry 38:9914–9925
Wang X, Ho RYN, Whiting AK, Que L Jr (1999) J Am Chem Soc 121:9235–9236
Cox RS, Schenk G, Mitic N, Gahan LR, Hengge AC (2007) J Am Chem Soc 129:9550–9551
Namgaladze D, Hofer HW, Ullrich V (2002) J Biol Chem 277:5962–5969
Ullrich V, Namgaladze D, Frein D (2003) Toxicol Lett 139:107–110
Wang DL, Holz RC, David SS, Que L Jr, Stankovich MT (1991) Biochemistry 30:8187–8194
Bernhardt PV, Schenk G, Wilson GJ (2004) Biochemistry 43:10387–10392
Yu L, Golbeck J, Yao J, Rusnak F (1997) Biochemistry 36:10727–10734
Zvelebil MJJM, Sternberg MJE (1988) Protein Eng 2:127–138
Lichtarge O, Bourne HR, Cohen FE (1996) J Mol Biol 257:342–358
Süel GM, Lockless SW, Wall MA, Ranganathan R (2002) Nat Struct Mol Biol 10:59–69
Pazos F, Valencia A (2008) EMBO J 27:2648–2655
Hirschi A, Cecchini M, Steinhardt RC, Schamber MR, Dick FA, Rubin SM (2010) Nat Struct Mol Biol 17:1051–1057
Huhn J, Jeffrey PD, Larsen K, Rundberget T, Rise F, Cox NR, Arcus V, Shi Y, Miles CO (2009) Chem Res Toxicol 22:1782–1786
Guddat LW, McAlpine AS, Hume D, Hamilton S, de Jersey J, Martin JL (1999) Structure 7:757–767
Uppenberg J, Lindqvist F, Svensson C, Ek-Rylander B, Andersson G (1999) J Mol Biol 290:201–211
Sträter N, Jasper B, Scholte M, Krebs B, Duff AP, Langley DB, Han R, Averill BA, Freeman HC, Guss JM (2005) J Mol Biol 351:233–246
Schenk G, Gahan LR, Carrington LE, Miti N, Valizadeh M, Hamilton SE, De Jersey J, Guddat LW (2005) Proc Natl Acad Sci USA 102:273–278
Li H, Zhang L, Rao A, Harrison S, Hogan P (2007) J Mol Biol 369:1296–1306
Larkin M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H, Valentin F, Wallace I, Wilm A, Lopez R (2007) Bioinformatics 23:2947–2948
Acknowledgment
This work was supported by a grant from National Natural Science Foundation of China (grant no. 21073014).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, H., Ma, Y., Liu, K. et al. Theoretical studies on the reaction mechanism of PP1 and the effects of different oxidation states of the Mn–Mn center on the mechanism. J Biol Inorg Chem 18, 451–459 (2013). https://doi.org/10.1007/s00775-013-0989-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00775-013-0989-1