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Human β-tryptase is a ring-like tetramer with active sites facing a central pore

Nature volume 392, pages 306–311 (1998)Cite this article

Abstract

Human tryptase, a mast-cell-specific serine proteinase that may be involved in causing asthma and other allergic and inflammatory disorders1,2,3, is unique in two respects: it is enzymatically active only as a heparin-stabilized tetramer, and it is resistant to all known endogenous proteinase inhibitors. The 3-Å crystal structure of human β-tryptase in a complex with 4-amidinophenyl pyruvic acid shows four quasi-equivalent monomers arranged in a square flat ring of pseudo 222 symmetry. Each monomer contacts its neighbours at two different interfaces through six loop segments. These loops are located around the active site of β-tryptase and differ considerably in length and conformation from loops of other trypsin-like proteinases. The four active centres of the tetramer are directed towards an oval central pore, restricting access for macromolecular substrates and enzyme inhibitors. Heparin chains might stabilize the complex by binding to an elongated patch of positively charged residues spanning two adjacent monomers. The nature of this unique tetrameric architecture explains many of tryptase's biochemical properties and provides a basis for the rational design of monofunctional and bifunctional tryptase inhibitors.

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Figure 1: Solid-surface representation of the tryptase tetramer.
Figure 2: Ribbon representation of one tryptase monomer in the standard orientation.
Figure 3: Structure-based amino-acid-sequence alignment.
Figure 4: Ribbon representation of the intermonomer contacts.
Figure 5: Section of the final 3.
Figure 6: Ribbon diagram of the tryptase-tetramer–LDTI complex.

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Acknowledgements

We thank D. Grosse for help in protein crystallization, R. Mentele for amino-acid-sequence analysis, and M. T. Stubbs for reading the paper. This work was supported by scholarships from Programa Praxis XXI of the Fundação para a Ciência e a Tecnologia and the Programa Gulbenkian de Doutoramento em Biologia e Medicina, Portugal, and by Biotech programs of the European Union, the Sonderforschungsbereich 469 of the University of Munich, the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.

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  1. Pedro José Barbosa Pereira, Andreas Bergner, Gabriele Matschiner, Hans Fritz and Christian P. Sommerhoff: These authors contributed equally to this work.

Authors and Affiliations

  1. Abteilung für Strukturforschung, Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152, Martinsried, Germany

    Pedro José Barbosa Pereira, Andreas Bergner, Sandra Macedo-Ribeiro, Robert Huber & Wolfram Bode

  2. Abteilung für Klinische Chemie und Klinische Biochemie in der Chirurgischen Klinik und Poliklinik, Klinikum Innenstadt der Ludwig-Maximilians-Universität, Nuβbaumstrasse 20, D-80336, Müchen, Germany

    Gabriele Matschiner, Hans Fritz & Christian P. Sommerhoff

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Correspondence to Wolfram Bode.

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Pereira, P., Bergner, A., Macedo-Ribeiro, S. et al. Human β-tryptase is a ring-like tetramer with active sites facing a central pore. Nature 392, 306–311 (1998). https://doi.org/10.1038/32703

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