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

Friedrich, Rainer, Panizzi, Peter, Fuentes-Prior, Pablo, Richter, Klaus, Verhamme, Ingrid, Anderson, Patricia J., Kawabata, Shun-Ichiro, Huber, Robert, Bode, Wolfram and Bock, Paul E. 2003. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 425 (6957) , pp. 535-539. 10.1038/nature01962

Full text not available from this repository.

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 alpha-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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Nature Publishing Group
ISSN:	0028-0836
Last Modified:	24 Jun 2017 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/70177

Citation Data

Cited 202 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item