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  • 1.
    Eklund, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Dogan, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kalbacher, Hubert
    Interfaculty institute of Biochemistry, University of Tübingen.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization of the endopeptidase activity of tripeptidyl-peptidase II2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 424, no 3, p. 503-507Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a giant cytosolic peptidase with a proposed role in cellular protein degradation and protection against apoptosis. Beside its well-characterised exopeptidase activity, TPP II also has an endopeptidase activity. Little is known about this activity, and since it could be important for the physiological role of TPP II, we have investigated it in more detail. Two peptides, Nef(69-87) and LL37, were incubated with wild-type murine TPP II and variants thereof as well as TPP II from human and Drosophila melanogaster. Two intrinsically disordered proteins were also included in the study. We conclude that the endopeptidase activity is more promiscuous than previously reported. It is also clear that TPP II can attack longer disordered peptides up to 75 amino acid residues. Using a novel FRET substrate, the catalytic efficiency of the endopeptidase activity could be determined to be 5 orders of magnitude lower than for the exopeptidase activity.

  • 2.
    Eklund, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lindås, Ann-Christin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hamnevik, Emil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Exploring the active site of tripeptidyl-peptidase II through studies of pH dependence of reaction kinetics2012In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1824, no 4, p. 561-570Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a subtilisin-like serine protease which forms a large enzyme complex (> 4 MDa). It is considered a potential drug target due to its involvement in specific physiological processes. However, information is scarce concerning the kinetic characteristics of TPP II and its active site features, which are important for design of efficient inhibitors. To amend this, we probed the active site by determining the pH dependence of TPP II catalysis. Access to pure enzyme is a prerequisite for kinetic investigations and herein we introduce the first efficient purification system for heterologously expressed mammalian TPP II. The pH dependence of kinetic parameters for hydrolysis of two different chromogenic substrates, Ala-Ala-Phe-pNA and Ala-Ala-Ala-pNA, was determined for murine, human and Drosophila melanogaster TPP II as well as mutant variants thereof. The investigation demonstrated that TPP II, in contrast to subtilisin, has a bell-shaped pH dependence of kcatapp/KM probably due to deprotonation of the N-terminal amino group of the substrate at higher pH. Since both the KM and kcatapp are lower for cleavage of AAA-pNA than for AAF-pNA we propose that the former can bind non-productively to the active site of the enzyme, a phenomenon previously observed with some substrates for subtilisin. Two mutant variants, H267A and D387G, showed bell-shaped pH-dependence of kcatapp, possibly due to an impaired protonation of the leaving group. This work reveals previously unknown differences between TPP II orthologues and subtilisin as well as features that might be conserved within the entire family of subtilisin-like serine peptidases.

  • 3.
    Eklund, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lindås, Ann-Christin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
    Hamnevik, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inter-species variation in the pH dependence of tripeptidyl-peptidase IIManuscript (preprint) (Other academic)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a large enzyme complex (>4 MDa) participating in the general protein turn-over in the cell downstream of the proteasome. In addition, there have been reports of involvement of TPP II in different physiological situations. To facilitate further investigations of the physiological role of TPP II and its enzymatic properties, a characterization at protein level is necessary. Therefore, an expression system for murine TPP II using Escherichia coli has been developed. The pH-optimum for cleavage of two different chromogenic substrates, Ala-Ala-Phe-pNA and Ala-Ala-Ala-pNA, was investigated for mTPP II, and compared with human TPP II and TPP II from Drosophila melanogaster. It was shown that the mouse enzyme had similar pH dependence as the human enzyme, while dTPP II had a slightly lower optimum. Surprisingly, the investigation also demonstrated that TPP II from all sources showed a different pH-profile for hydrolysis of AAA-pNA compared to AAF-pNA. To investigate this observation further, steady-state kinetic parameters were determined at various pH. Since both the KM and Vmax are lower for cleavage of AAA-pNA, a potential explanation could be that the substrate AAA-pNA is non-productively bound to the active site of the enzyme.

  • 4.
    Eklund, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Structure, Function and Evolution of a Giant Enzyme, Tripeptidyl-Peptidase II2012In: Serine proteases: mechanism, structure and evolution / [ed] Isamu Chiba & Takao Kamio, Nova Science Publishers, Inc., 2012, p. 55-70Chapter in book (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a giant exopeptidase with an active site of the subtilisin-type. Its main function is to remove tripeptides from a free N-terminal end of longer peptides. TPP II is active at neutral pH and is dependent on the same catalytic triad as other subtilases, i.e. Asp-44, His-264 and Ser-449 (numbering for murine TPP II). Furthermore, Glu-331 has been shown to be important for binding the N-terminal amino group of the substrate. Besides its exopeptidase activity, TPP II also appears to have a low endopeptidase activity. The large subunit (138 kDa in humans) forms a >4 MDa. Oligomerisation is essential for full enzymatic activity. The recently determined hybrid structure of the TPP II spindle from Drosophila melanogaster demonstrated that the active site is localized inside the spindle and that it is a self-compartmentalizing enzyme. TPP II is present in most eukaryotes, but has not been detected in archea and the homologous genes that appear in prokaryotes are suggested to be the result of a horizontal gene transfer. A role for TPP II in degradation of the neuropeptide cholecystokinin has been suggested, and the enzyme appears to be involved in trimming of some substrates for antigen presentation. However, considering its widespread distribution, this is probably not its main physiological function. A more reasonable assumption is that the enzyme has evolved to participate in a general protein turnover in the cytosol of most cells, presumably together with the proteasome and other peptidases. 

  • 5.
    Eriksson, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Gutierrez Arenas, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Bjerling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Development, evaluation and application of tripeptidyl-peptidase II sequence signatures2009In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 484, no 1, p. 39-45Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a cytosolic peptidase that has been implicated in fat formation and cancer, apparently independent of the enzymatic activity. In search for alternative functional regions, conserved motifs were identified and eleven signatures were constructed. Seven of the signatures covered previously investigated residues, whereas the functional importance of the other motifs is unknown. This provides directions for future investigations of alternative activities of TPP II. The obtained signatures provide an efficient bioinformatic tool for the identification of TPP II homologues. Hence, a TPP II sequence homologue from fission yeast, Schizosaccharomyces pombe, was identified and demonstrated to encode the TPP II-like protein previously reported as multicorn. Furthermore, an homologous protein was found in the prokaryote Blastopirellula marina, albeit the TPP II function was apparently not conserved. This gene is probably the result of a rare gene transfer from eukaryote to prokaryote.

  • 6.
    Hibli, Hibert
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Jozsa, Emese
    Tomkinson, Birgitta
    Identification of the catalytic triad in tripeptidyl-peptidase II trough site-directed mutagenesis2002In: Biochimica et Biophysica Acta, Vol. 1601, p. 149-154Article in journal (Refereed)
  • 7. Kessler, Jan H.
    et al.
    Khan, Selina
    Seifert, Ulrike
    Le Gall, Sylvie
    Chow, K .Martin
    Paschen, Annette
    Bres-Vloemans, Sandra A.
    de Ru, Arnoud
    van Montfoort, Nadine
    Franken, Kees L.M.C.
    Benckhuijsen, Willemien E.
    Brooks, Jill M.
    van Hall, Thorbald
    Ray, Kallol
    Mulder, Arend
    Doxiadis, Ilias I. N.
    van Swieten, Paul F.
    Overkleeft, Hermen S.
    Prat, Annik
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neefjes, Jacques
    Kloetzel, Peter M.
    Rodgers, David W.
    Hersh, Louis B.
    Drijfhout, Jan W.
    van Veelen, Peter A.
    Ossendorp, Ferry
    Melief, Cornelis J. M.
    Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes2010In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 12, no 1, p. 45-53Article in journal (Refereed)
    Abstract [en]

    Cytotoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C terminus of these CTL epitopes is considered to be produced by the proteasome. Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus protein EBNA3C, and a clinically important epitope from the melanoma protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing, and nardilysin contributed to both the C-terminal and N-terminal generation of CTL epitopes. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.

  • 8.
    Lindås, Ann-Christin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Eriksson, Sandra
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Jozsa, Emese
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Investigation of a role for Glu-331 and Glu-305 in substrate binding of tripeptidyl-peptidase II2008In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1784, no 12, p. 1899-1907Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the mechanism by which tripeptidyl-peptidase II (TPP II) can specifically release tripeptides from the free N-terminus of an oligopeptide. The subtilisin-like N-terminal part of TPP II was modelled using subtilisin as template. Two glutamate residues (Glu-305 and Glu-331) appeared to be positioned so as to interact with the positively charged N-terminus of the substrate. In order to test this potential interaction, both residues were replaced by glutamine and lysine. The catalytic efficiency was reduced 400-fold for the E331Q variant and 20000-fold for the E331K variant, compared with the wild-type (wt). A substantial part of this reduction was due to decreased substrate affinity, since the K(M) for both mutants was at least two orders of magnitude greater than for the wt. This decrease was linked specifically to interaction with the free N-terminal amino group, based on inhibition studies. Glu-305 appears to be essential for enzymatic activity, but the extremely low activity of the E305Q variant prevented an investigation of the involvement of Glu-305 in substrate binding. The present work is, to our knowledge, the first report to investigate a mechanism for a tripeptidyl-peptidase activity through site-directed mutagenesis.

  • 9.
    Lindås, Ann-Christin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization of the promoter of the gene encoding human tripeptidyl-peptidase II and identification of upstream silencer elements2007In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 393, no 1-2, p. 62-69Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is one of the many proteases involved in the important process of intracellular proteolysis. The widespread distribution and broad substrate specificity suggest that TPP II is encoded by a "house-keeping gene". However, both TPP II protein and mRNA levels vary in different cells. To investigate whether these variations are due to regulation on a genetic level, the promoter of the TPP2 gene has previously been identified. The promoter contains two inverted CCAAT-boxes and an E-box. By means of reporter assays and electrophoretic mobility shift assays the promoter has now been further characterized. It could be concluded that USF-1 (upstream stimulatory factor-1) binds to the E-box in the promoter. The transcription factors NF-Y and USF-1 are present in protein-DNA complexes of different sizes. Mutation of the E-box had no effect, indicating that only binding of NF-Y to the two CCAAT-boxes was important for activation of transcription. However, this does not exclude the possibility that USF-1 can play an important role in transcription in other types of cells. Furthermore, the region upstream of the promoter was investigated due to its ability to inhibit transcription. Several silencer elements were identified and we also showed that Oct-1 binds to one of these elements. Thus, this investigation reveals that TPP II expression could be regulated through both positive and negative regulatory elements. Further studies are required to establish the involvement of different genetic elements, and how the interplay between different transcription factors will affect the transcriptional rate in vivo.

  • 10.
    Lindås, Ann-Christin
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Tomkinson, Birgitta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Identification and characterization of the promoter for the gene encoding human tripeptidyl-peptidase II.2005In: Gene, ISSN 0378-1119, Vol. 345, no 2, p. 249-57Article in journal (Refereed)
  • 11.
    Nahálková, Jarmila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    TPPII, MYBBP1A and CDK2 form a protein–protein interaction network2014In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 564, p. 128-135Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPPII) is an aminopeptidase with suggested regulatory effects on cell cycle, apoptosis and senescence. A protein–protein interaction study revealed that TPPII physically interacts with the tumor suppressor MYBBP1A and the cell cycle regulator protein CDK2. Mutual protein–protein interaction was detected between MYBBP1A and CDK2 as well. In situ Proximity Ligation Assay (PLA) using HEK293 cells overexpressing TPPII forming highly enzymatically active oligomeric complexes showed that the cytoplasmic interaction frequency of TPPII with MYBBP1A increased with the protein expression of TPPII and using serum-free cell growth conditions. A specific reversible inhibitor of TPPII, butabindide, suppressed the cytoplasmic interactions of TPPII and MYBBP1A both in control HEK293 and the cells overexpressing murine TPPII. The interaction of MYBBP1A with CDK2 was confirmed by in situPLA in two different mammalian cell lines. Functional link between TPPII and MYBBP1A has been verified by gene expression study during anoikis, where overexpression of TPP II decreased mRNA expression level of MYBBP1A at the cell detachment conditions. All three interacting proteins TPPII, MYBBP1A and CDK2 have been previously implicated in the research for development of tumor-suppressing agents. This is the first report presenting mutual protein–protein interaction network of these proteins.

  • 12. Radu, Diana
    et al.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Zachrisson, Olof
    Weber, Günther
    de Belleroche, Jacqueline
    Hirsch, Steven
    Lindefors, Nils
    Overlapping regional distribution of CCK and TPPII mRNAs in Cynomolgus monkey brain and correlated levels in human cerebral cortex (BA 10)2006In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1104, no 1, p. 175-182Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl peptidase II (TPPII) is a high molecular weight exopeptidase important in inactivating extracellular cholecystokinin (CCK). Our aims were to study the anatomical localization of TPPII and CCK mRNA in the Cynomolgus monkey brain as a basis for a possible functional anatomical connection between enzyme (TPPII) and substrate (CCK) and examine if indications of changes in substrate availability in the human brain might be reflected in changes of levels of TPPII mRNA. Methods: mRNA in situ hybridization on postmortem brain from patients having had a schizophrenia diagnosis as compared to controls and on monkey and rat brain slices. Results: overlapping distribution patterns of mRNAs for TPPII and CCK in rat and monkey. High amounts of TPPII mRNA are seen in the neocortex, especially in the frontal region and the hippocampus. TPPII mRNA is also present in the basal ganglia and cerebellum where CCK immunoreactivity and/or CCK B receptors have been found in earlier studies, suggesting presence of CCK-ergic afferents from other brain regions. Levels of mRNAs for CCK and TPPII show a positive correlation in postmortem human cerebral cortex Brodmann area (BA) 10. TPPII mRNA might be affected following schizophrenia. Discussion: overall TPPII and CCK mRNA show a similar distribution in rat and monkey brain, confirming and extending earlier studies in rodents, In addition, correlated levels of TPPII and CCK mRNA in human BA 10 corroborate a functional link between CCK and TPPII in the human brain.

  • 13.
    Reinthaler, E. M.
    et al.
    Med Univ Vienna, Inst Neurol, Vienna, Austria..
    Graf, E.
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany..
    Zrzavy, T.
    Med Univ Vienna, Ctr Brain Res, Vienna, Austria..
    Wieland, T.
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany..
    Hotzy, C.
    Med Univ Vienna, Inst Neurol, Vienna, Austria..
    Kopecky, C.
    Med Univ Vienna, Dept Internal Med 3, Div Nephrol & Dialysis, Vienna, Austria..
    Schmied, C.
    Med Univ Vienna, Inst Neurol, Vienna, Austria..
    Leutmezer, F.
    Med Univ Vienna, Inst Neurol, Vienna, Austria..
    Keilani, M.
    Med Univ Vienna, Dept Phys Med & Rehabil, Vienna, Austria..
    Lill, C. M.
    Univ Lubeck, Dept Neurol, Focus Program Translat Neurosci, Lubeck, Germany..
    Hoffjan, S.
    Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany..
    Epplen, J. T.
    Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany..
    Zettl, U. K.
    Univ Rostock, Neuroimmunol Sect, Dept Neurol, Rostock, Germany..
    Hecker, M.
    Univ Rostock, Neuroimmunol Sect, Dept Neurol, Rostock, Germany..
    Deutschlaender, A.
    Univ Wurzburg, Dept Neurol, Wurzburg, Germany..
    Ahram, M.
    Univ Jordan, Dept Physiol & Biochem, Amman, Jordan..
    Mustafa, B.
    Univ Jordan, Dept Physiol & Biochem, Amman, Jordan..
    El-Khateeb, M.
    Univ Jordan, NCDEG, Amman, Jordan..
    Vilarino-Guell, C.
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada..
    Sadovnick, D. A.
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada..
    Zimprich, F.
    Med Univ Vienna, Inst Neurol, Vienna, Austria..
    Tomkinson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden..
    Strom, T. M.
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany..
    Kristoferitsch, W.
    SMZ Ost Donauspital, Karl Landsteiner Inst Neuroimmunol & Neurodegener, Vienna, Austria..
    Lassmann, H.
    Med Univ Vienna, Ctr Brain Res, Vienna, Austria..
    Zimprich, A.
    Med Univ Vienna, Inst Neurol, Vienna, Austria..
    Mutations in the gene tripeptidyl peptidase II (TPP2) and multiple sclerosis2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, no suppl. 3, p. 849-849Article in journal (Refereed)
  • 14.
    Reinthaler, Eva M.
    et al.
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Graf, Elisabeth
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
    Zrzavy, Tobias
    Med Univ Vienna, Ctr Brain Res, Vienna, Austria.
    Wieland, Thomas
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
    Hotzy, Christoph
    Kopecky, Chantal
    Med Univ Vienna, Dept Internal Med 3, Div Nephrol & Dialysis, Vienna, Austria.
    Pferschy, Sandra
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Schmied, Christiane
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Leutmezer, Fritz
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Keilani, Mohammad
    Med Univ Vienna, Rehabil & Occupat Med, Dept Phys Med, Vienna, Austria.
    Lill, Christina M.
    Univ Lubeck, Inst Neurogenet & Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Focus Program Translat Neurosci FTN, Dept Neurol, Mainz, Germany;Johannes Gutenberg Univ Mainz, Univ Med Ctr, Neuroimaging Ctr NIC, Mainz, Germany.
    Hoffjan, Sabine
    Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany.
    Epplen, Joerg T.
    Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany;Univ Witten, Fac Hlth, ZBAF, Herdecke, Witten, Germany.
    Zettl, Uwe K.
    Univ Rostock, Neuroimmunol Sect, Dept Neurol, Rostock, Germany.
    Hecker, Michael
    Univ Rostock, Neuroimmunol Sect, Dept Neurol, Rostock, Germany.
    Deutschlaender, Angela
    Jeweils Mayo Clin, Dept Neurol, Jacksonville, FL USA;Jeweils Mayo Clin, Dept Clin Genom, Jacksonville, FL USA;Jeweils Mayo Clin, Dept Neurosci, Jacksonville, FL USA.
    Meuth, Sven G.
    Univ Munster, Dept Neurol, Munster, Germany.
    Ahram, Mamoun
    Univ Jordan, Sch Med, Dept Physiol & Biochem, Amman, Jordan.
    Mustafa, Baha
    Univ Jordan, Sch Med, Dept Physiol & Biochem, Amman, Jordan.
    El-Khateeb, Mohammed
    Natl Ctr Inst Diabet, Endocrinol & Genet NCDEG, Amman, Jordan.
    Vilarino-Guell, Cartes
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Sadovnick, Dessa
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada.
    Zimprich, Fritz
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Strom, Tim
    Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany.
    Kristoferitsch, Wolfgang
    SMZ Ost Donauspital, Karl Landsteiner Inst Neuroimmunol & Neurodegener, Vienna, Austria;SMZ Ost Donauspital, Inst Neuroimmunol & Neurodegenerat Disorders, Vienna, Austria.
    Lassmann, Hans
    Med Univ Vienna, Ctr Brain Res, Vienna, Austria.
    Zimprich, Alexander
    Med Univ Vienna, Dept Neurol, Vienna, Austria.
    TPP2 mutation associated with sterile brain inflammation mimicking MS2018In: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 4, no 6, article id UNSP e285Article in journal (Refereed)
    Abstract [en]

    Objective To ascertain the genetic cause of a consanguineous family from Syria suffering from a sterile brain inflammation mimicking a mild nonprogressive form of MS.

    Methods We used homozygosity mapping and next-generation sequencing to detect the disease-causing gene in the affected siblings. In addition, we performed RNA and protein expression studies, enzymatic activity assays, immunohistochemistry, and targeted sequencing of further MS cases from Austria, Germany, Canada and Jordan.

    Results In this study, we describe the identification of a homozygous missense mutation (c.82T>G, p.Cys28Gly) in the tripeptidyl peptidase II (TPP2) gene in all 3 affected siblings of the family. Sequencing of all TPP2-coding exons in 826 MS cases identified one further homozygous missense variant (c.2027C>T, p.Thr676Ile) in a Jordanian MS patient. TPP2 protein expression in whole blood was reduced in the affected siblings. In contrast, TPP2 protein expression in postmortem brain tissue from MS patients without TPP2 mutations was highly upregulated.

    Conclusions The homozygous TPP2 mutation (p.Cys28Gly) is likely responsible for the inflammation phenotype in this family. TPP2 is an ubiquitously expressed serine peptidase that removes tripeptides from the N-terminal end of longer peptides. TPP2 is involved in various biological processes including the destruction of major histocompatibility complex Class I epitopes. Recessive loss-of-function mutations in TPP2 were described in patients with Evans syndrome, a rare autoimmune disease affecting the hematopoietic system. Based on the gene expression results in our MS autopsy brain samples, we further suggest that TPP2 may play a broader role in the inflammatory process in MS.

  • 15. Stavropoulou, Vaia
    et al.
    Xie, Jianjun
    Henriksson, Marie
    Tomkinson, Birgitta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Imreh, Stefan
    Masucci, Maria G
    Mitotic infidelity and centrosome duplication errors in cells overexpressing tripeptidyl-peptidase II.2005In: Cancer Res, ISSN 0008-5472, Vol. 65, no 4, p. 1361-8Article in journal (Refereed)
  • 16.
    Tomkinson, B
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Association and dissociation of the tripeptidyl-peptidase II complex as a way of regulating the enzyme activity2000In: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, ISSN 0003-9861, Vol. 376, no 2, p. 275-280Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II is an unusually large exopeptidase. The subunits (M-r = 138,000) form an active complex with an M-r > 10(6). This paper demonstrates that the complex can spontaneously dissociate in vitro into dimers which retain 1/10th of the ori

  • 17.
    Tomkinson, Birgitta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Tripeptidyl peptidases: enzymes that count.1999In: Trends Biochem Sci, ISSN 0968-0004, Vol. 24, no 9, p. 355-9Article, review/survey (Other (popular scientific, debate etc.))
  • 18.
    Tomkinson, Birgitta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Tripeptidyl-peptidase II2004In: Handbook of proteolytic enzymes, Elsevier Academic Press, Amsterdam , 2004, p. 1882-1885Chapter in book (Other scientific)
  • 19.
    Tomkinson, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eklund, Sandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tripeptidyl-peptidase II2012In: Handbook of Proteolytic Enzymes volume 1 / [ed] Neil D. Rawlings & Guy S. Salvesen, Elsevier, 2012, 3, p. 3325-3331Chapter in book (Refereed)
  • 20.
    Tomkinson, Birgitta
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Lindås, Ann-Christin
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
    Tripeptidyl-peptidase II: a multi-purpose peptidase.2005In: Int J Biochem Cell Biol, ISSN 1357-2725, Vol. 37, no 10, p. 1933-7Article, review/survey (Other (popular scientific, debate etc.))
    Abstract [en]

    Tripeptidyl-peptidase II is a high-molecular weight peptidase with a widespread distribution in eukaryotic cells. The enzyme sequentially removes tripeptides from a free N-terminus of longer peptides and also displays a low endopeptidase activity. A role for tripeptidyl-peptidase II in the formation of peptides for antigen presentation has recently become evident, and the enzyme also appears to be important for the degradation of some specific substrates, e.g. the neuropeptide cholecystokinin. However, it is likely that the main biological function of tripeptidyl-peptidase II is to participate in a general intracellular protein turnover. This peptidase may act on oligopeptides generated by the proteasome, or other endopeptidases, and the tripeptides formed would subsequently be good substrates for other exopeptidases. The fact that tripeptidyl-peptidase II activity is increased in sepsis-induced muscle wasting, a situation of enhanced protein turnover, corroborates this biological role.

  • 21.
    Tomkinson, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Ni Laoi, Bairbre
    Wellington, Kimberly
    The insert within the catalytic domain of tripeptidyl-peptidase II is important for the formation of the active complex2002In: European Journal of Biochemistry, Vol. 269, p. 1438-1443Article in journal (Refereed)
  • 22. Tomkinson, Birgitta
    et al.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Distribution of tripeptidyl-peptidase II in the central nervous system of rat1995In: Neurochemical Research, ISSN 0364-3190, E-ISSN 1573-6903, Vol. 20, no 12, p. 1443-1447Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl-peptidase II (TPP II) is a high molecular weight serine peptidase which removes tripeptides from a free N-terminus of longer peptides. Since it had previously been demonstrated that the enzyme can inactivate enkephalins and dynorphins in vitro by removing the N-terminal Tyr-Gly-Gly peptide, we wanted to see whether TPP II could be involved in this process also in vivo. Therefore, the localization of TPP II in different cerebral regions of rat was investigated by immunoblot analysis and activity measurements. It could be shown that TPP II is relatively evenly distributed in the central nervous system of rat. This indicates that the physiological role of the enzyme is probably not a specific degradation of enkephalins, but rather pertains to the general turnover of proteins.

  • 23. Wiemhoefer, Anne
    et al.
    Stargardt, Anita
    van der Linden, Wouter A.
    Renner, Maria C.
    van Kesteren, Ronald E.
    Stap, Jan
    Raspe, Marcel A.
    Tomkinson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kessels, Helmut W.
    Ovaa, Huib
    Overkleeft, Herman S.
    Florea, Bogdan
    Reits, Eric A.
    Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK22015In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 14, no 8, p. 2177-2193Article in journal (Refereed)
    Abstract [en]

    Tripeptidyl peptidase II (TPP2) is a serine peptidase involved in various biological processes, including antigen processing, cell growth, DNA repair, and neuropeptide mediated signaling. The underlying mechanisms of how a peptidase can influence this multitude of processes still remain unknown. We identified rapid proteomic changes in neuroblastoma cells following selective TPP2 inhibition using the known reversible inhibitor butabindide, as well as a new, more potent, and irreversible peptide phosphonate inhibitor. Our data show that TPP2 inhibition indirectly but rapidly decreases the levels of active, di-phosphorylated extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the nucleus, thereby down-regulating signal transduction downstream of growth factors and mitogenic stimuli. We conclude that TPP2 mediates many important cellular functions by controlling ERK1 and ERK2 phosphorylation. For instance, we show that TPP2 inhibition of neurons in the hippocampus leads to an excessive strengthening of synapses, indicating that TPP2 activity is crucial for normal brain function.

  • 24.
    Wray, Curtis J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Tomkinson, Birgitta
    Robb, Bruce W.
    Hasselgren, Per-Olof
    Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis2002In: Biochemical and Biophysical Research Communications, Vol. 296, no 1, p. 41-47Article in journal (Refereed)
1 - 24 of 24
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