The von Willebrand factor-binding protein (vWbp) of Staphylococcus aureus is a coagulase

Bjerketorp, Joakim; Jacobsson, Karin; Frykberg, Lars

doi:10.1016/j.femsle.2004.03.040

Cited by 70 publications

(98 citation statements)

References 13 publications

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“…Deletion of Ile 1 in SC(2-325) showed only a ~6-fold loss of apparent affinity, whereas SC(3-325) exhibited <2% prothrombin activator activity. These results demonstrated the specificity of conformational activation for the N-terminal Ile-Val dipeptide of SC, and also highlighted the unexpected tolerance of the Ile 16 cleft of prothrombin for structurally different N-termini, consistent with the recent observation that SC containing an additional N-terminal Ala clots human plasma [31]. This apparent polyandry shown by prothrombin for the altered N-terminus of SC is unlike the strict requirement for the N-terminal Ile 1 residue on SK for conformational activation of plasminogen [26].…”

Section: Proof Of the Molecular Sexuality Hypothesissupporting

confidence: 87%

“…vWbp is bifunctional, with N-terminal domains [vWbp (1-262)] exhibiting non-proteolytic prothrombin activator activity [P. Panizzi and P. E. Bock, unpublished observations]; [1] and clotting of human plasma [31], and a C-terminal sequence that mediates binding to vWf [32]. vWbp is predicted to interact with (pro)exosite I, which may affect the protein substrate specificity of the vWbp•(pro)thrombin complex, as does SC(1-325).…”

Section: Vwf Binding Protein (Vwbp) and The New Zaap Familymentioning

confidence: 99%

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The staphylocoagulase family of zymogen activator and adhesion proteins

Panizzi

Friedrich

Fuentes‐Prior

et al. 2004

CMLS, Cell. Mol. Life Sci.

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Staphylocoagulase (SC) secreted by Staphylococcus aureus is a potent non-proteolytic activator of the blood coagulation zymogen prothrombin and the prototype of a newly established zymogen activator and adhesion protein (ZAAP) family. The conformationally activated SC•prothrombin complex specifically cleaves fibrinogen to fibrin, which propagates the growth of bacteria-fibrinplatelet vegetations in acute bacterial endocarditis. Our recent 2.2 Å X-ray crystal structures of an active SC fragment [SC(1-325)] bound to the prothrombin zymogen catalytic domain, prethrombin 2, demonstrated that SC(1-325) represents a new type of non-proteolytic activator with a unique fold. The observed insertion of the SC(1-325) N-terminus into the 'Ile 16' cleft of prethrombin 2, which triggers the activating conformational change, provided the first unambiguous structural evidence for the 'molecular sexuality' mechanism of non-proteolytic zymogen activation. Based on the SC(1-325) fold, a new family of bifunctional zymogen activator and adhesion proteins was identified that possess N-terminal domains homologous to SC(1-325) and C-terminal domains that mediate adhesion to plasma or extracellular matrix proteins. Further investigation of the ZAAP family may lead to new insights into the mechanisms of bacterial factors that hijack zymogens of the human blood coagulation and fibrinolytic systems to promote and disseminate endocarditis and other infectious diseases.

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Section: Proof Of the Molecular Sexuality Hypothesissupporting

confidence: 87%

Section: Vwf Binding Protein (Vwbp) and The New Zaap Familymentioning

confidence: 99%

The staphylocoagulase family of zymogen activator and adhesion proteins

Panizzi

Friedrich

Fuentes‐Prior

et al. 2004

CMLS, Cell. Mol. Life Sci.

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“…VWbp was further recognized as a putative member of the bifunctional zymogen activator and adhesion protein (ZAAP) family for which SC is the prototype (12,13). It was subsequently postulated to be an SC homolog from its 25% sequence identity with SC and clotting of human plasma (14).…”

mentioning

confidence: 99%

Von Willebrand factor-binding protein is a hysteretic conformational activator of prothrombin

Kroh

Panizzi

Bock

2009

Proc. Natl. Acad. Sci. U.S.A.

102

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Von Willebrand factor-binding protein (VWbp), secreted by Staphylococcus aureus, displays secondary structural homology to the 3-helix bundle, D1 and D2 domains of staphylocoagulase (SC), a potent conformational activator of the blood coagulation zymogen, prothrombin (ProT). In contrast to the classical proteolytic activation mechanism of trypsinogen-like serine proteinase zymogens, insertion of the first 2 residues of SC into the NH 2-terminal binding cleft on ProT (molecular sexuality) induces rapid conformational activation of the catalytic site. Based on plasma-clotting assays, the target zymogen for VWbp may be ProT, but this has not been verified, and the mechanism of ProT activation is unknown. We demonstrate that VWbp activates ProT conformationally in a mechanism requiring its Val 1 -Val 2 residues. By contrast to SC, full time-course kinetic studies of ProT activation by VWbp demonstrate that it activates ProT by a substrate-dependent, hysteretic kinetic mechanism. VWbp binds weakly to ProT (K D 2.5 M) to form an inactive complex, which is activated through a slow conformational change by tripeptide chromogenic substrates and its specific physiological substrate, identified here as fibrinogen (Fbg). This mechanism increases the specificity of ProT activation by delaying it in a slow reversible process, with full activation requiring binding of Fbg through an exosite expressed on the activated ProT*⅐VWbp complex. The results suggest that this unique mechanism regulates pathological fibrin (Fbn) deposition to VWF-rich areas during S. aureus endocarditis.coagulation ͉ proteinases ͉ Staphylococcus aureus ͉ zymogens ͉ hysteresis

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“…S. aureus has evolved remarkable strategies to hijack the coagulation cascade, allowing the organism to convert this host defense mechanism into a protective fibrin sheath that supports survival and replication (144). This process is primarily mediated by coagulase (Coa) and von Willebrand factor-binding protein (vWbp) (145), both of which bind and activate prothrombin, resulting in thrombin complexes that cleave fibrinogen to generate a bacterial-derived coating of host fibrin (146). Importantly, while Coa and vWbp both activate prothrombin, they are both required for virulence in models of bacteremia and abscess formation, indicating distinct functions in the manipulation of host coagulation (147).…”

Section: Adaptations To the Host Environmentmentioning

confidence: 99%