Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation

Rainer Friedrich, Peter Panizzi, Pablo Fuentes-Prior, Klaus Richter, Ingrid Verhamme, Patricia J. Anderson, Shun-Ichiro Kawabata, Robert Huber, Wolfram Bode () and Paul E. Bock ()
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Rainer Friedrich: Max-Planck-Institut für Biochemie
Peter Panizzi: Vanderbilt University School of Medicine, C3321A Medical Center North
Pablo Fuentes-Prior: Max-Planck-Institut für Biochemie
Klaus Richter: Technische Universität München
Ingrid Verhamme: Vanderbilt University School of Medicine, C3321A Medical Center North
Patricia J. Anderson: Vanderbilt University School of Medicine, C3321A Medical Center North
Shun-Ichiro Kawabata: Kyushu University
Robert Huber: Max-Planck-Institut für Biochemie
Wolfram Bode: Max-Planck-Institut für Biochemie
Paul E. Bock: Vanderbilt University School of Medicine, C3321A Medical Center North

Nature, 2003, vol. 425, issue 6957, 535-539

Abstract: Abstract Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems1,2. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis3, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting4,5. Here we present the 2.2 Å crystal structures of human α-thrombin and prethrombin-2 bound to a fully active staphylocoagulase variant. The cofactor consists of two domains, each with three-helix bundles; this is a novel fold that is distinct from known serine proteinase activators, particularly the streptococcal plasminogen activator streptokinase6. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors7,8,9. Kinetic studies confirm the importance of isoleucine 1 and valine 2 at the amino terminus of staphylocoagulase for zymogen activation. In addition to making contacts with the 148 loop and (pro)exosite I of prethrombin-2, staphylocoagulase inserts its N-terminal peptide into the activation pocket of bound prethrombin-2, allosterically inducing functional catalytic machinery. These investigations demonstrate unambiguously the validity of the zymogen-activation mechanism known as ‘molecular sexuality’10.

Date: 2003
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DOI: 10.1038/nature01962

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