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Tomkinson, Birgitta
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Publications (10 of 24) Show all publications
Reinthaler, E. M., Graf, E., Zrzavy, T., Wieland, T., Hotzy, C., Kopecky, C., . . . Zimprich, A. (2018). TPP2 mutation associated with sterile brain inflammation mimicking MS. NEUROLOGY-GENETICS, 4(6), Article ID UNSP e285.
Open this publication in new window or tab >>TPP2 mutation associated with sterile brain inflammation mimicking MS
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2018 (English)In: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 4, no 6, article id UNSP e285Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-376411 (URN)10.1212/NXG.0000000000000285 (DOI)000455099800009 ()30533531 (PubMedID)
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved
Reinthaler, E. M., Graf, E., Zrzavy, T., Wieland, T., Hotzy, C., Kopecky, C., . . . Zimprich, A. (2016). Mutations in the gene tripeptidyl peptidase II (TPP2) and multiple sclerosis. Paper presented at 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), SEP 14-17, 2016, London, ENGLAND. Multiple Sclerosis, 22(suppl. 3), 849-849
Open this publication in new window or tab >>Mutations in the gene tripeptidyl peptidase II (TPP2) and multiple sclerosis
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2016 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, no suppl. 3, p. 849-849Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2016
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-320118 (URN)000383267203282 ()
Conference
32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), SEP 14-17, 2016, London, ENGLAND
Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2017-04-21Bibliographically approved
Wiemhoefer, A., Stargardt, A., van der Linden, W. A., Renner, M. C., van Kesteren, R. E., Stap, J., . . . Reits, E. A. (2015). Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2. Molecular & Cellular Proteomics, 14(8), 2177-2193
Open this publication in new window or tab >>Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2
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2015 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 14, no 8, p. 2177-2193Article in journal (Refereed) Published
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.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-260825 (URN)10.1074/mcp.M114.043331 (DOI)000358837400011 ()26041847 (PubMedID)
Available from: 2015-08-27 Created: 2015-08-25 Last updated: 2018-01-11Bibliographically approved
Nahálková, J. & Tomkinson, B. (2014). TPPII, MYBBP1A and CDK2 form a protein–protein interaction network. Archives of Biochemistry and Biophysics, 564, 128-135
Open this publication in new window or tab >>TPPII, MYBBP1A and CDK2 form a protein–protein interaction network
2014 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 564, p. 128-135Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
TPPII, MYBBP1A, CDK2, Cell cycle, Apoptosis
National Category
Biochemistry and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-235245 (URN)10.1016/j.abb.2014.09.017 (DOI)000346222600015 ()25303791 (PubMedID)
Available from: 2014-10-30 Created: 2014-10-30 Last updated: 2017-12-05Bibliographically approved
Eklund, S., Dogan, J., Jemth, P., Kalbacher, H. & Tomkinson, B. (2012). Characterization of the endopeptidase activity of tripeptidyl-peptidase II. Biochemical and Biophysical Research Communications - BBRC, 424(3), 503-507
Open this publication in new window or tab >>Characterization of the endopeptidase activity of tripeptidyl-peptidase II
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2012 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 424, no 3, p. 503-507Article in journal (Refereed) Published
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.

Keywords
TPP II, endopeptidase, alternate activity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-134620 (URN)10.1016/j.bbrc.2012.06.144 (DOI)000307618800024 ()
Available from: 2010-11-30 Created: 2010-11-30 Last updated: 2017-12-12Bibliographically approved
Eklund, S., Lindås, A.-C., Hamnevik, E., Widersten, M. & Tomkinson, B. (2012). Exploring the active site of tripeptidyl-peptidase II through studies of pH dependence of reaction kinetics. Biochimica et Biophysica Acta - Proteins and Proteomics, 1824(4), 561-570
Open this publication in new window or tab >>Exploring the active site of tripeptidyl-peptidase II through studies of pH dependence of reaction kinetics
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2012 (English)In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1824, no 4, p. 561-570Article in journal (Refereed) Published
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.

Keywords
tripeptidyl-peptidase II, AAF-pNA, AAA-pNA, steady-state kinetics, pH-dependence
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-166875 (URN)10.1016/j.bbapap.2012.01.004 (DOI)000302443000004 ()
Available from: 2012-01-16 Created: 2012-01-16 Last updated: 2017-12-08Bibliographically approved
Eklund, S. & Tomkinson, B. (2012). Structure, Function and Evolution of a Giant Enzyme, Tripeptidyl-Peptidase II. In: Isamu Chiba & Takao Kamio (Ed.), Serine proteases: mechanism, structure and evolution (pp. 55-70). Nova Science Publishers, Inc.
Open this publication in new window or tab >>Structure, Function and Evolution of a Giant Enzyme, Tripeptidyl-Peptidase II
2012 (English)In: 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. 

Place, publisher, year, edition, pages
Nova Science Publishers, Inc., 2012
Series
Cell biology research progress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-197693 (URN)978-1-61942-669-6 (ISBN)
Available from: 2013-04-15 Created: 2013-04-02 Last updated: 2013-04-15Bibliographically approved
Tomkinson, B. & Eklund, S. (2012). Tripeptidyl-peptidase II (3ed.). In: Neil D. Rawlings & Guy S. Salvesen (Ed.), Handbook of Proteolytic Enzymes volume 1 (pp. 3325-3331). Elsevier
Open this publication in new window or tab >>Tripeptidyl-peptidase II
2012 (English)In: Handbook of Proteolytic Enzymes volume 1 / [ed] Neil D. Rawlings & Guy S. Salvesen, Elsevier, 2012, 3, p. 3325-3331Chapter in book (Refereed)
Place, publisher, year, edition, pages
Elsevier, 2012 Edition: 3
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-197692 (URN)10.1016/B978-0-12-382219-2.00734-1 (DOI)
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2013-04-02Bibliographically approved
Kessler, J. H., Khan, S., Seifert, U., Le Gall, S., Chow, K. .. a., Paschen, A., . . . Melief, C. J. M. (2010). Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunology, 12(1), 45-53
Open this publication in new window or tab >>Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes
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2010 (English)In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 12, no 1, p. 45-53Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-138776 (URN)10.1038/ni.1974 (DOI)000285465100012 ()21151101 (PubMedID)
Note

Peter A van Veelen, Ferry Ossendorp & Cornelis J M Melief contributed equally to this work.

Available from: 2010-12-20 Created: 2010-12-20 Last updated: 2017-12-11Bibliographically approved
Eriksson, S., Gutierrez Arenas, O., Bjerling, P. & Tomkinson, B. (2009). Development, evaluation and application of tripeptidyl-peptidase II sequence signatures. Archives of Biochemistry and Biophysics, 484(1), 39-45
Open this publication in new window or tab >>Development, evaluation and application of tripeptidyl-peptidase II sequence signatures
2009 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 484, no 1, p. 39-45Article in journal (Refereed) Published
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.

Keywords
Serine protease, subtilase, sequence motif, cytosolic protein degradation, tripeptidyl-peptidase II
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-119529 (URN)10.1016/j.abb.2009.01.007 (DOI)000264927700006 ()19467630 (PubMedID)
Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12
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