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Structural Studies on PP2A and Methods in Protein Production

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Structural Studies on PP2A and Methods in Protein Production Structural studies on PP2A and Methods in Protein Production Auður Magnúsdóttir ©Auður Magnúsdóttir, pp.1-53, Stockholm 2008 ISBN 978-91-7155-750-6 Printed in Sweden by Universitetsservice AB, Stockholm 2008 Distributor: Department of Biochemistry and Biophysics, Stock- holm University All previously published papers are reprinted with permission from the publisher To Elski Pelski Abstract PP2A is a major phosphatase in the cell that participates in multiple cell signaling pathways. It is a heterotrimer of a core dimer and variable regulatory subunits. Details of its structure, function and regulation are slowly emerging. Here, the structure of two regulators of PP2A are de- scribed; PTPA and B56γ. PTPA is a highly conserved enzyme that plays a crucial role in PP2A activity but whose biochemical function is still unclear. B56γ is a PP2A regulatory subunit linked to cancer and the structure pre- sented here of B56γ in its free form is particularly valuable in light of the recent structures of the PP2A holoenzyme and core dimer. Protein production is a major bottleneck in structural genomic pro- jects. Here, we describe two novel methods for improved protein produc- tion. The first is a colony based screening method where any DNA library can be screened for soluble expression of recombinant proteins in E.coli. The second method involves improvements of the well established IMAC purification method. We have seen that a low molecular weight component of E.coli lysate decreases the binding capacity of IMAC columns and by removing the low molecular weight components, recombinant proteins only present at low levels in E.coli lysate can be purified, which has previously been believed to be unfeasible. Contents Introduction ................................................................................................11 Macromolecular Structures......................................................................................11 Scope of the Thesis ...................................................................................................12 Protein phosphatase 2A ...........................................................................13 Ser/thr dephosphorylation.......................................................................................13 Biochemical properties........................................................................................15 Cellular role of PP2A ............................................................................................19 Structural studies of PTPA .......................................................................................21 Biological role of PTPA.........................................................................................21 Structure of PTPA .................................................................................................22 The structure of the PP2A regulatory subunit B56γ ..........................................25 Structure of the free B56γ .................................................................................26 B56γ in its free and holoenzyme forms ..........................................................28 Holoenzyme assembly.........................................................................................28 Methods in Protein Production................................................................31 Escherichia coli as an expression host..................................................................31 Structural genomics and protein production .......................................................32 The CoFi blot...............................................................................................................32 Procedure of the CoFi blot..................................................................................33 Screening of an DNA library with the CoFi blot .............................................34 Limitations to IMAC...................................................................................................34 IMAC and the 6xhis tag ......................................................................................34 Migration of a target protein on IMAC columns.............................................35 Desalting of lysate before loading on IMAC ...................................................35 Who is to blame?..................................................................................................38 Summary.....................................................................................................40 Future perspective ....................................................................................42 References ..................................................................................................45 List of Publications Magnusdottir, A., Stenmark, P., Flodin, S., Nyman, T., Kotenyova, T., Gräslund, S., Ogg, D., and Nordlund, P. (2008) The structure of the PP2A regulatory subunit B56gamma: The remaining piece of the PP2A jigsaw puzzle. Proteins: Structure, Function, and Bioinformatics, In press (avail- able online as of 10th July 2008) Magnusdottir, A. Johansson, I.,Dalhgren, L-G., Bakali, A., Nordlund, P. and Berglund, H. (2008) IMAC purification has severe and serious limi- tations. Means for improvement. Manuscript Magnusdottir, A., Stenmark, P., Flodin, S., Nyman, T., Hammarstrom, M., Ehn, M., Bakali-H, M.A., Berglund, H. and Nordlund, P. (2006) The crystal structure of a human PP2A phosphatase activator reveals a novel fold and highly conserved cleft implicated in protein-protein interactions. Journal of Biological Chemistry, 281: p. 22434-22438 Cornvik, T., Dahlroth, S.L., Magnusdottir, A., Flodin, S., Engvall, B., Lieu, V., Ekberg, M., and Nordlund P. (2006) An efficient and generic strategy for producing soluble human proteins and domains in E. coli by screening construct libraries. Proteins-Structure Function and Bioinformat- ics, 65: p. 266-273 Cornvik, T., Dahlroth, S.L., Magnusdottir, A., Herman, M.D., Knaust, R., Ekberg, M. and Nordlund P. (2005) Colony filtration blot: a new screening method for soluble protein expression in Escherichia coli. Nature Methods, 2: p. 507-9 Additional publications S. El-Andaloussi, H. Johansson, A. Magnusdottir, P. Jarver, P. Lundberg, and U. Langel. (2005) TP10, a delivery vector for decoy oligonucleotides targeting the Myc protein. Journal of Controlled Release, 110: p.189-201. A. Magnusdottir, M. Masson, T. Loftsson. (2002) Self Association and Cyclodextrin Solibilization of NSAIDs. Journal of inclusion phenomena and Macrocyclic Chemistry, 44: p. 213-218 T. Loftsson, A. Magnusdottir, M. Masson and J.F. Sigurjonsdottir. (2002) Self-Association and Cyclodextrin Solubilization of Drugs. Journal of Pharmaceutical Sciences 91 (11): p. 2307-2316 H.H. Sigurdsson, A. Magnusdottir, M. Masson, T.Loftsson. (2002) The Effects of Cyclodextrins on Hydrocortisone Permeability Through Semi- Permeable Membranes. Journal of inclusion phenomena and Macrocyclic Chemistry, 44: p. 163-167 Abbreviations 6xhis Hexahistidine fusion tag E. coli Escherichia coli GFP Green Fluorescent Protein IMAC Immobilized Metal Affinity Chromatography IRL Intra repeat loop PP2A Protein Phosphatase 2A PP2Aa Structural subunit of PP2A PP2Ab Regulatory subunit of PP2A PP2Ac Catalytic subunit of PP2A PP2Ad PP2A core dimer of PP2Aa and PP2Ac PTPA PP2A phosphatase activator PPIase Peptidyl prolyl cis/trans isomerase PME-1 PP2A methyl esterase 1 SGP Structural genomics project Introduction Macromolecular Structures Information about the three dimensional structure of biological mac- romolecules is vital for understanding their function at the molecular level. Although the role of structural biology has not been as dominating in drug design as first expected it has become increasingly important in other fields of the life sciences and has now regained ground in drug discovery. The large number of structures now available of different biologically relevant macromolecules; proteins, nucleic acids and viruses, and complexes thereof has brought this about. Structural biology is no longer a narrow field of a few eccentrics with generous amount of time (it took 22 years to determine the first protein structure); rather it is an indispensable tool in the under- standing of the molecular mechanisms of life. Despite the difficulties in obtaining protein crystals and other chal- lenges such as missing phase information, twinning and weak diffracting crystals, X-ray crystallography continues to be the dominating method for high-resolution structure determination of macromolecules. On the 50th an- niversary of the first protein structure, X-ray crystallography is still used for the ab initio determination of the majority of macromolecular structures and 85%, of all structures in the PDB are determined with X-ray crystallography (figure 1). Other methods used to obtain 3D structures of macromolecules, NMR and electron microscopy, are limited to lower molecular mass proteins and low resolution, respectively. However, the three methods are to some extent complementary; NMR can provide dynamic and kinetic information and electron microscopy is well suited for the study of large macromolecular assemblies (Branden and Tooze, 1999; Manjasetty et al., 2008; McPherson, 2003). 11 Figure 1: The number of entries in the protein data bank each year of this millen- nium in total and by experimental method. In 1990, 508 structures had been submit- ted to the PDB, on August 19th, 2008 this number was 52535. Scope of the Thesis The thesis
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