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The crystal structure of the proprotein processing proteinase furin explains its stringent specificity

Nature Structural & Molecular Biology volume 10, pages 520–526 (2003)Cite this article

An Addendum to this article was published on 01 August 2003

Abstract

In eukaryotes, many essential secreted proteins and peptide hormones are excised from larger precursors by members of a class of calcium-dependent endoproteinases, the prohormone-proprotein convertases (PCs). Furin, the best-characterized member of the mammalian PC family, has essential functions in embryogenesis and homeostasis but is also implicated in various pathologies such as tumor metastasis, neurodegeneration and various bacterial and viral diseases caused by such pathogens as anthrax and pathogenic Ebola virus strains. Furin cleaves protein precursors with narrow specificity following basic Arg-Xaa-Lys/Arg-Arg-like motifs. The 2.6 Å crystal structure of the decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk)–inhibited mouse furin ectodomain, the first PC structure, reveals an eight-stranded jelly-roll P domain associated with the catalytic domain. Contoured surface loops shape the active site by cleft, thus explaining furin's stringent requirement for arginine at P1 and P4, and lysine at P2 sites by highly charge-complementary pockets. The structure also explains furin's preference for basic residues at P3, P5 and P6 sites. This structure will aid in the rational design of antiviral and antibacterial drugs.

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Figure 1: Primary structure of mouse furin.
Figure 2: Overall three-dimensional structure of mouse furin.
Figure 3: Fold differences between subtilisin and the catalytic domain of furin.
Figure 4: Interactions between the inhibitor and the active site cleft.
Figure 5: A model of substrate interaction with furin.

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Acknowledgements

The technical help of H. Bartunik and R. Mentele and the financial support of a National Institutes of Health grant and a Research Scientist Development Award (I.L.), a DFG grant (M.E.T.), the SFB596, the Fonds der Chemischen Industrie and EU-projects (W.B.) are gratefully acknowledged. The authors wish to thank D. Steiner for establishing the contact for this collaboration.

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  1. Angus Cameron

    Present address: Department of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom

Authors and Affiliations

  1. Max-Planck-Institut für Biochemie, Abt. Strukturforschung, Am Klopferspitz 18A, Martinsried, 82152, Germany

    Stefan Henrich, Reiner Kiefersauer, Robert Huber, Wolfram Bode & Manuel E Than

  2. Department of Biochemistry & Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, 70112, Louisiana, USA

    Angus Cameron & Iris Lindberg

  3. Max-Planck-Arbeitsgruppen für Strukturelle Molekularbiologie (MPG-ASMB), Gruppe Proteindynamik, DESY, Notkestrasse 85, Hamburg, 22603, Germany

    Gleb P Bourenkov

  4. Proteros Biostructures GmbH, Am Klopferspitz 19, Martinsried, 82152, Germany

    Reiner Kiefersauer

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Correspondence to Wolfram Bode or Manuel E Than.

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Henrich, S., Cameron, A., Bourenkov, G. et al. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Mol Biol 10, 520–526 (2003). https://doi.org/10.1038/nsb941

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