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, Paul E. Bock

研究成果: ジャーナルへの寄稿記事

155 引用 (Scopus)

抄録

Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting. 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 streptokinase. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors. 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 zymogenactivation mechanism known as 'molecular sexuality'.

元の言語英語
ページ(範囲)535-539
ページ数5
ジャーナルNature
425
発行部数6957
DOI
出版物ステータス出版済み - 10 2 2003

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Enzyme Precursors
Coagulase
Blood Coagulation
Trypsinogen
Streptokinase
Bacterial Proteins
Isoleucine
Plasminogen Activators
Valine
Sexuality
Serine Proteases
Prothrombin
Fibrinolysis
Endocarditis
Protein Binding
Thrombin
Extracellular Matrix
Staphylococcus aureus
Blood Proteins
Sepsis

All Science Journal Classification (ASJC) codes

  • General

これを引用

Friedrich, R., Panizzi, P., Fuentes-Prior, P., Richter, K., Verhamme, I., Anderson, P. J., ... Bock, P. E. (2003). Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature, 425(6957), 535-539. https://doi.org/10.1038/nature01962

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; Bock, Paul E.

:: Nature, 巻 425, 番号 6957, 02.10.2003, p. 535-539.

研究成果: ジャーナルへの寄稿記事

Friedrich, R, Panizzi, P, Fuentes-Prior, P, Richter, K, Verhamme, I, Anderson, PJ, Kawabata, S-I, Huber, R, Bode, W & Bock, PE 2003, 'Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation', Nature, 巻. 425, 番号 6957, pp. 535-539. https://doi.org/10.1038/nature01962
Friedrich R, Panizzi P, Fuentes-Prior P, Richter K, Verhamme I, Anderson PJ その他. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature. 2003 10 2;425(6957):535-539. https://doi.org/10.1038/nature01962
Friedrich, Rainer ; Panizzi, Peter ; Fuentes-Prior, Pablo ; Richter, Klaus ; Verhamme, Ingrid ; Anderson, Patricia J. ; Kawabata, Shun-Ichiro ; Huber, Robert ; Bode, Wolfram ; Bock, Paul E. / Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. :: Nature. 2003 ; 巻 425, 番号 6957. pp. 535-539.
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abstract = "Many bacterial pathogens secrete proteins that activate host trypsinogen-like enzyme precursors, most notably the proenzymes of the blood coagulation and fibrinolysis systems. Staphylococcus aureus, an important human pathogen implicated in sepsis and endocarditis, secretes the cofactor staphylocoagulase, which activates prothrombin, without the usual proteolytic cleavages, to directly initiate blood clotting. Here we present the 2.2 {\AA} 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 streptokinase. The staphylocoagulase fold is conserved in other bacterial plasma-protein-binding factors and extracellular-matrix-binding factors. 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 zymogenactivation mechanism known as 'molecular sexuality'.",
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