Mechanostability of the Fibrinogen Bridge between Staphylococcal Surface Protein ClfA and Endothelial Cell Integrin αVß3.
Nano Lett
; 19(10): 7400-7410, 2019 10 09.
Article
em En
| MEDLINE
| ID: mdl-31532212
ABSTRACT
Binding of the Staphylococcus aureus surface protein clumping factor A (ClfA) to endothelial cell integrin αVß3 plays a crucial role during sepsis, by causing endothelial cell apoptosis and loss of barrier integrity. ClfA uses the blood plasma protein fibrinogen (Fg) to bind to αVß3 but how this is achieved at the molecular level is not known. Here we investigate the mechanical strength of the three-component ClfA-Fg-αVß3 interaction on living bacteria, by means of single-molecule experiments. We find that the ClfA-Fg-αVß3 ternary complex is extremely stable, being able to sustain forces (â¼800 pN) that are much stronger than those of classical bonds between integrins and the Arg-Gly-Asp (RGD) tripeptide sequence (â¼100 pN). Adhesion forces between single bacteria and αVß3 are strongly inhibited by an anti-αVß3 antibody, the RGD peptide, and the cyclic RGD peptide cilengitide, showing that formation of the complex involves RGD-dependent binding sites and can be efficiently inhibited by αVß3 blockers. Collectively, our experiments favor a binding mechanism involving the extraordinary elasticity of Fg. In the absence of mechanical stress, RGD572-574 sequences in the Aα chains mediate weak binding to αVß3, whereas under high mechanical stress exposure of cryptic Aα chain RGD95-97 sequences leads to extremely strong binding to the integrin. Our results identify an unexpected and previously undescribed force-dependent binding mechanism between ClfA and αVß3 on endothelial cells, which could represent a potential target to fight staphylococcal bloodstream infections.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Staphylococcus aureus
/
Fibrinogênio
/
Coagulase
/
Integrina alfaVbeta3
/
Células Endoteliais
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Bélgica