A novel von Willebrand factor binding protein expressed by Staphylococcus aureus
            
               
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                  aThe GenBank accession number for the sequence reported in this paper is AY032850.

Bjerketorp, Joakim; Nilsson, Marie; Ljungh, Åsa; Flock, Jan‐Ingmar; Jacobsson, Karin; Frykberg, Lars

doi:10.1099/00221287-148-7-2037

Cited by 91 publications

(69 citation statements)

References 39 publications

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“…This raises the question of why are there 2 ProT activators, VWbp and SC, secreted by S. aureus. All S. aureus strains that contain the gene for VWbp also contain the gene for SC (11). The evolutionary advantage responsible for maintaining both activators is likely because of the differences in the adhesion protein targets and the kinetic mechanisms of ProT activation.…”

Section: Discussionmentioning

confidence: 99%

“…Binding to both immobilized and soluble VWF is mediated by a 26-aa region within VWbp (11), but the physiological significance of this interaction has not been established. 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).…”

mentioning

confidence: 99%

“…Von Willebrand factor-binding protein (VWbp), also secreted by S. aureus, was first identified by phage-display of an S. aureus (Newman) DNA library screened against von Willebrand factor (VWF) (11), leading to its classification as an adhesion protein.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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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“…Domain organization of ZAAPs. SC homologs are S. agalactiae proteins CAD46494 [34]; NP_687847 [33]; SfbX, Streptococcus pyogenes fibronectin (FN)-binding protein [37]; and vWbp [32]. The sequence that directs cell-wall sorting of SfbX is indicated by a diamond; the RGD triplet is also indicated.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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The Use of Phage Display in Neurobiology

Bradbury

2010

CP Neuroscience

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Phage display has been extensively used to study protein-protein interactions, receptor- and antibody-binding sites, and immune responses, to modify protein properties, and to select antibodies against a wide range of different antigens. In the format most often used, a polypeptide is displayed on the surface of a filamentous phage by genetic fusion to one of the coat proteins, creating a chimeric coat protein, and coupling phenotype (the protein) to genotype (the gene within). As the gene encoding the chimeric coat protein is packaged within the phage, selection of the phage on the basis of the binding properties of the polypeptide displayed on the surface simultaneously results in the isolation of the gene encoding the polypeptide. This unit describes the background to the technique, and illustrates how it has been applied to a number of different problems, each of which has its neurobiological counterparts. Although this overview concentrates on the use of filamentous phage, which is the most popular platform, other systems are also described.

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A novel von Willebrand factor binding protein expressed by Staphylococcus aureus a aThe GenBank accession number for the sequence reported in this paper is AY032850.

Cited by 91 publications

References 39 publications

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

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

The staphylocoagulase family of zymogen activator and adhesion proteins

The Use of Phage Display in Neurobiology

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