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Development, evaluation and application of tripeptidyl-peptidase II sequence signatures
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics. (Department of Biochemistry and Organic Chemistry. Uppsala University.)ORCID iD: 0000-0003-3522-0196
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2009 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 484, no 1, 39-45 p.Article 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.

Place, publisher, year, edition, pages
2009. Vol. 484, no 1, 39-45 p.
Keyword [en]
Serine protease, subtilase, sequence motif, cytosolic protein degradation, tripeptidyl-peptidase II
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-119529DOI: 10.1016/j.abb.2009.01.007ISI: 000264927700006PubMedID: 19467630OAI: oai:DiVA.org:uu-119529DiVA: diva2:300389
Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12
In thesis
1. Interpreting a Giant: Studies of Structure and Function of Tripeptidyl-peptidase II
Open this publication in new window or tab >>Interpreting a Giant: Studies of Structure and Function of Tripeptidyl-peptidase II
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tripeptidyl-peptidase II (TPP II) is a subtilisin-like serine peptidase that forms a gigantic homooligomeric complex, and is involved in the degradation of peptides in the cytosol. In addition, TPP II has been implicated in specific cellular processes, such as apoptosis control and adipogenesis, but if this is dependent on its endo- or exopeptidase activity remains to be determined. This work is devoted to the structure and function of TPP II, and to finding connections between the two.

Evolutionarily conserved regions of TPP II have been identified, and sequence signatures have been constructed as an aid in identification of TPP II homologues. The conserved regions highlight amino acid residues of potential importance to structure, function or both. In addition, the first TPP II homologue in a prokaryote has been documented, which was likely the result of a horizontal gene transfer.

Substrate binding for the exopeptidase activity of TPP II has been studied through mutagenesis of Glu-331, which revealed a molecular ruler mechanism that positions substrates for cleavage at the third peptide bond from the N-terminus. Thus, the well-known tripeptidyl-releasing property of TPP II could be explained. The exopeptidase activity was also probed by pH dependence studies, which revealed that a substrate with a smaller residue in the P1 position could bind non-productively to the active site. Furthermore, a difference in the pH dependence of KM between TPP II from Drosophila and homologues from mammals indicated a difference in the configuration of the binding pockets between these species.

The endopeptidase activity of TPP II has also been investigated, and was found to differ from the exopeptidase activity. The endopeptidase activity appeared to be promiscuous and the preference for basic amino acid residues in the P1 position reported earlier could not be substantiated.

In conclusion, many structural and mechanistic features have been observed in this work. This might be of value to future drug discovery efforts towards TPP II, and in elucidating the physiological role of this gigantic enzyme.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 791
Keyword
Tripeptidyl-peptidas II, molecular ruler, sequence signatures, pH-dependence, endopeptidase
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-134633 (URN)978-91-554-7966-4 (ISBN)
Public defence
2011-01-21, B7:101a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note
Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 721Available from: 2010-12-22 Created: 2010-11-30 Last updated: 2011-03-21Bibliographically approved

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Gutierrez Arenas, OmarBjerling, PernillaTomkinson, Birgitta

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