Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions
Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
5 May 2015
|
| In: |
Biophysical journal
Year: 2015, Volume: 108, Issue: 9, Pages: 2312-2321 |
| ISSN: | 1542-0086 |
| DOI: | 10.1016/j.bpj.2015.03.041 |
| Online Access: | Verlag, teilw. kostenfrei, Volltext: http://dx.doi.org/10.1016/j.bpj.2015.03.041 Verlag, teilw. kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S0006349515003021 
|
| Author Notes: | Camilo Aponte-Santamaría, Volker Huck, Sandra Posch, Agnieszka K. Bronowska, Sandra Grässle, Maria A. Brehm, Tobias Obser, Reinhard Schneppenheim, Peter Hinterdorfer, Stefan W. Schneider, Carsten Baldauf, and Frauke Gräter |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1566560004 | ||
| 003 | DE-627 | ||
| 005 | 20250206094532.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 171219s2015 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bpj.2015.03.041 |2 doi | |
| 035 | |a (DE-627)1566560004 | ||
| 035 | |a (DE-576)49656000X | ||
| 035 | |a (DE-599)BSZ49656000X | ||
| 035 | |a (OCoLC)1340983790 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Aponte-Santamaria, Camilo |e VerfasserIn |0 (DE-588)1078084343 |0 (DE-627)837949491 |0 (DE-576)448880628 |4 aut | |
| 245 | 1 | 0 | |a Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions |c Camilo Aponte-Santamaría, Volker Huck, Sandra Posch, Agnieszka K. Bronowska, Sandra Grässle, Maria A. Brehm, Tobias Obser, Reinhard Schneppenheim, Peter Hinterdorfer, Stefan W. Schneider, Carsten Baldauf, and Frauke Gräter |
| 264 | 1 | |c 5 May 2015 | |
| 300 | |a 10 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 19.12.2017 | ||
| 520 | |a Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and its coupling to cleavage under shear-forces in flowing blood remain unknown. In this study, we describe, to our knowledge, a new force-sensory mechanism for VWF-platelet binding, which addresses these questions, based on a combination of molecular dynamics (MD) simulations, atomic force microscopy (AFM), and microfluidic experiments. Our MD simulations demonstrate that the VWF A2 domain targets a specific region at the VWF A1 domain, corresponding to the binding site of the platelet glycoprotein Ibα (GPIbα) receptor, thereby causing its blockage. This implies autoinhibition of the VWF for the binding of platelets mediated by the A1-A2 protein-protein interaction. During force-probe MD simulations, a stretching force dissociated the A1A2 complex, thereby unblocking the GPIbα binding site. Dissociation was found to be coupled to the unfolding of the A2 domain, with dissociation predominantly occurring before exposure of the cleavage site in A2, an observation that is supported by our AFM experiments. This suggests that the A2 domain prevents platelet binding in a force-dependent manner, ensuring that VWF initiates hemostasis before inactivation by proteolytic cleavage. Microfluidic experiments with an A2-deletion VWF mutant resulted in increased platelet binding, corroborating the key autoinhibitory role of the A2 domain within VWF multimers. Overall, autoinhibition of VWF mediated by force-dependent interdomain interactions offers the molecular basis for the shear-sensitive growth of VWF-platelet aggregates, and might be similarly involved in shear-induced VWF self-aggregation and other force-sensing functions in hemostasis. | ||
| 700 | 1 | |a Huck, Volker |d 1978- |e VerfasserIn |0 (DE-588)134286537 |0 (DE-627)692230297 |0 (DE-576)300425651 |4 aut | |
| 700 | 1 | |a Grässle, Sandra |d 1986- |e VerfasserIn |0 (DE-588)1038287863 |0 (DE-627)756930367 |0 (DE-576)392277603 |4 aut | |
| 700 | 1 | |a Brehm, Maria A. |e VerfasserIn |0 (DE-588)1047229390 |0 (DE-627)777876795 |0 (DE-576)400578719 |4 aut | |
| 700 | 1 | |a Obser, Tobias |e VerfasserIn |0 (DE-588)1027416403 |0 (DE-627)729117847 |0 (DE-576)373203365 |4 aut | |
| 700 | 1 | |a Schneppenheim, Reinhard |d 1950- |e VerfasserIn |0 (DE-588)109434900 |0 (DE-627)592607070 |0 (DE-576)303538031 |4 aut | |
| 700 | 1 | |a Schneider, Stefan W. |d 1966- |e VerfasserIn |0 (DE-588)137570546 |0 (DE-627)593664868 |0 (DE-576)304124702 |4 aut | |
| 700 | 1 | |a Baldauf, Carsten |d 1977- |e VerfasserIn |0 (DE-588)130420115 |0 (DE-627)501124284 |0 (DE-576)189378042 |4 aut | |
| 700 | 1 | |a Gräter, Frauke |e VerfasserIn |0 (DE-588)130664871 |0 (DE-627)505296764 |0 (DE-576)298331314 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biophysical journal |d Cambridge, Mass. : Cell Press, 1960 |g 108(2015), 9, Seite 2312-2321 |h Online-Ressource |w (DE-627)270425357 |w (DE-600)1477214-0 |w (DE-576)091017602 |x 1542-0086 |7 nnas |a Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions |
| 773 | 1 | 8 | |g volume:108 |g year:2015 |g number:9 |g pages:2312-2321 |g extent:10 |a Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bpj.2015.03.041 |x Verlag |x Resolving-System |z teilw. kostenfrei |3 Volltext |
| 856 | 4 | 0 | |u http://www.sciencedirect.com/science/article/pii/S0006349515003021 |x Verlag |z teilw. kostenfrei |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20171219 | ||
| 993 | |a Article | ||
| 994 | |a 2015 | ||
| 998 | |g 130664871 |a Gräter, Frauke |m 130664871:Gräter, Frauke |d 700000 |d 708000 |d 700000 |d 718000 |e 700000PG130664871 |e 708000PG130664871 |e 700000PG130664871 |e 718000PG130664871 |k 0/700000/ |k 1/700000/708000/ |k 0/700000/ |k 1/700000/718000/ |p 12 |y j | ||
| 998 | |g 1038287863 |a Grässle, Sandra |m 1038287863:Grässle, Sandra |d 60000 |d 61900 |e 60000PG1038287863 |e 61900PG1038287863 |k 0/60000/ |k 1/60000/61900/ |p 5 | ||
| 998 | |g 134286537 |a Huck, Volker |m 134286537:Huck, Volker |d 60000 |d 61900 |e 60000PH134286537 |e 61900PH134286537 |k 0/60000/ |k 1/60000/61900/ |p 2 | ||
| 999 | |a KXP-PPN1566560004 |e 2990371613 | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"note":["Gesehen am 19.12.2017"],"origin":[{"dateIssuedDisp":"5 May 2015","dateIssuedKey":"2015"}],"recId":"1566560004","relHost":[{"name":{"displayForm":["ed. by the Biophysical Society"]},"language":["eng"],"id":{"zdb":["1477214-0"],"eki":["270425357"],"issn":["1542-0086"]},"origin":[{"publisherPlace":"Cambridge, Mass. ; Bethesda, Md. ; New York, NY","dateIssuedKey":"1960","dateIssuedDisp":"1960-","publisher":"Cell Press ; Soc. ; Rockefeller Univ. Press"}],"note":["Gesehen am 20.05.2020"],"pubHistory":["1.1960/61 -"],"recId":"270425357","type":{"bibl":"periodical","media":"Online-Ressource"},"title":[{"subtitle":"BJ","title_sort":"Biophysical journal","title":"Biophysical journal"}],"part":{"volume":"108","extent":"10","issue":"9","year":"2015","pages":"2312-2321","text":"108(2015), 9, Seite 2312-2321"},"disp":"Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactionsBiophysical journal","physDesc":[{"extent":"Online-Ressource"}],"corporate":[{"display":"Biophysical Society","role":"isb"}],"titleAlt":[{"title":"BJ"}]}],"type":{"bibl":"article-journal","media":"Online-Ressource"},"name":{"displayForm":["Camilo Aponte-Santamaría, Volker Huck, Sandra Posch, Agnieszka K. Bronowska, Sandra Grässle, Maria A. Brehm, Tobias Obser, Reinhard Schneppenheim, Peter Hinterdorfer, Stefan W. Schneider, Carsten Baldauf, and Frauke Gräter"]},"language":["eng"],"person":[{"given":"Camilo","display":"Aponte-Santamaria, Camilo","role":"aut","family":"Aponte-Santamaria"},{"family":"Huck","display":"Huck, Volker","given":"Volker","role":"aut"},{"family":"Grässle","display":"Grässle, Sandra","given":"Sandra","role":"aut"},{"role":"aut","display":"Brehm, Maria A.","given":"Maria A.","family":"Brehm"},{"role":"aut","display":"Obser, Tobias","given":"Tobias","family":"Obser"},{"role":"aut","given":"Reinhard","display":"Schneppenheim, Reinhard","family":"Schneppenheim"},{"family":"Schneider","role":"aut","display":"Schneider, Stefan W.","given":"Stefan W."},{"family":"Baldauf","given":"Carsten","display":"Baldauf, Carsten","role":"aut"},{"role":"aut","display":"Gräter, Frauke","given":"Frauke","family":"Gräter"}],"title":[{"title_sort":"Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions","title":"Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions"}],"id":{"doi":["10.1016/j.bpj.2015.03.041"],"eki":["1566560004"]},"physDesc":[{"extent":"10 S."}]} | ||
| SRT | |a APONTESANTFORCESENSI5201 | ||