Autoregulation of von Willebrand factor function by a disulfide bond switch

Diego Butera, Freda Passam, Lining Ju, Kristina M. Cook, Heng Woon, Camilo Aponte-Santamaría, Elizabeth Gardiner, Amanda K. Davis, Deirdre A. Murphy, Agnieszka Bronowska, Brenda M. Luken, Carsten Baldauf, Shaun Jackson, Robert Andrews, Frauke Gräter, Philip J. Hogg

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Abstract

Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ∼75% of VWF subunits in healthy human donor plasma but in just ∼25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.

Original languageEnglish
Article numbereaaq1477
Number of pages13
JournalScience Advances
Volume4
Issue number2
DOIs
Publication statusPublished - 28 Feb 2018

Cite this

Butera, D., Passam, F., Ju, L., Cook, K. M., Woon, H., Aponte-Santamaría, C., ... Hogg, P. J. (2018). Autoregulation of von Willebrand factor function by a disulfide bond switch. Science Advances, 4(2), [eaaq1477]. https://doi.org/10.1126/sciadv.aaq1477
Butera, Diego ; Passam, Freda ; Ju, Lining ; Cook, Kristina M. ; Woon, Heng ; Aponte-Santamaría, Camilo ; Gardiner, Elizabeth ; Davis, Amanda K. ; Murphy, Deirdre A. ; Bronowska, Agnieszka ; Luken, Brenda M. ; Baldauf, Carsten ; Jackson, Shaun ; Andrews, Robert ; Gräter, Frauke ; Hogg, Philip J. / Autoregulation of von Willebrand factor function by a disulfide bond switch. In: Science Advances. 2018 ; Vol. 4, No. 2.
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title = "Autoregulation of von Willebrand factor function by a disulfide bond switch",
abstract = "Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this {"}mechanopresentation{"} remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ∼75{\%} of VWF subunits in healthy human donor plasma but in just ∼25{\%} of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.",
author = "Diego Butera and Freda Passam and Lining Ju and Cook, {Kristina M.} and Heng Woon and Camilo Aponte-Santamar{\'i}a and Elizabeth Gardiner and Davis, {Amanda K.} and Murphy, {Deirdre A.} and Agnieszka Bronowska and Luken, {Brenda M.} and Carsten Baldauf and Shaun Jackson and Robert Andrews and Frauke Gr{\"a}ter and Hogg, {Philip J.}",
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Butera, D, Passam, F, Ju, L, Cook, KM, Woon, H, Aponte-Santamaría, C, Gardiner, E, Davis, AK, Murphy, DA, Bronowska, A, Luken, BM, Baldauf, C, Jackson, S, Andrews, R, Gräter, F & Hogg, PJ 2018, 'Autoregulation of von Willebrand factor function by a disulfide bond switch', Science Advances, vol. 4, no. 2, eaaq1477. https://doi.org/10.1126/sciadv.aaq1477

Autoregulation of von Willebrand factor function by a disulfide bond switch. / Butera, Diego; Passam, Freda; Ju, Lining; Cook, Kristina M.; Woon, Heng; Aponte-Santamaría, Camilo; Gardiner, Elizabeth; Davis, Amanda K.; Murphy, Deirdre A.; Bronowska, Agnieszka; Luken, Brenda M.; Baldauf, Carsten; Jackson, Shaun; Andrews, Robert; Gräter, Frauke; Hogg, Philip J.

In: Science Advances, Vol. 4, No. 2, eaaq1477, 28.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Autoregulation of von Willebrand factor function by a disulfide bond switch

AU - Butera, Diego

AU - Passam, Freda

AU - Ju, Lining

AU - Cook, Kristina M.

AU - Woon, Heng

AU - Aponte-Santamaría, Camilo

AU - Gardiner, Elizabeth

AU - Davis, Amanda K.

AU - Murphy, Deirdre A.

AU - Bronowska, Agnieszka

AU - Luken, Brenda M.

AU - Baldauf, Carsten

AU - Jackson, Shaun

AU - Andrews, Robert

AU - Gräter, Frauke

AU - Hogg, Philip J.

PY - 2018/2/28

Y1 - 2018/2/28

N2 - Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ∼75% of VWF subunits in healthy human donor plasma but in just ∼25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.

AB - Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ∼75% of VWF subunits in healthy human donor plasma but in just ∼25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.

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U2 - 10.1126/sciadv.aaq1477

DO - 10.1126/sciadv.aaq1477

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Butera D, Passam F, Ju L, Cook KM, Woon H, Aponte-Santamaría C et al. Autoregulation of von Willebrand factor function by a disulfide bond switch. Science Advances. 2018 Feb 28;4(2). eaaq1477. https://doi.org/10.1126/sciadv.aaq1477