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Structure of von Willebrand factor A1 on polystyrene determined from experimental and calculated sum frequency generation spectra.

ABSTRACT: The blood-clotting protein von Willebrand factor (vWF) can be activated by small molecules, high shear stress, and interactions with interfaces. It subsequently binds platelet receptor glycoprotein Ib? (GPIb?) at the surface of platelets, thereby playing a crucial role in blood clotting due to platelet activation, which is an important process to consider in the design of cardiovascular implants and biomaterials used in blood-contacting applications. The influence of surfaces on the activation and the molecular-level structure of surface-bound vWF is largely unknown. Recent studies have indicated that when bound to hydrophobic polystyrene (PS), the A1 domain of vWF remains accessible for GPIb? binding. However, the detailed secondary structure and exact orientation of vWF A1 at the PS surface is still unresolved. Here, the authors resolve these features by studying the system with sum-frequency generation (SFG) spectroscopy. The data are consistent with a scenario where vWF A1 maintains a native secondary structure when bound to PS. Comparison of experimental and calculated SFG spectra combined with previously reported time-of-flight secondary ion mass spectrometry data suggests that A1 assumes an orientation with the GPIb? binding domain oriented away from the solid surface and exposed to the solution phase. This structural information will benefit future in vitro experiments with surface-adsorbed A1 domain and may have relevance for the design of novel blood-contacting biomaterials and wound-healing applications.

SUBMITTER: Roeters SJ

PROVIDER: S-EPMC6294649 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Structure of von Willebrand factor A1 on polystyrene determined from experimental and calculated sum frequency generation spectra.

Roeters Steven J SJ Tronic Elaine H EH Baio Joe E JE Castner David G DG Weidner Tobias T

Biointerphases 20181214 6

The blood-clotting protein von Willebrand factor (vWF) can be activated by small molecules, high shear stress, and interactions with interfaces. It subsequently binds platelet receptor glycoprotein Ibα (GPIbα) at the surface of platelets, thereby playing a crucial role in blood clotting due to platelet activation, which is an important process to consider in the design of cardiovascular implants and biomaterials used in blood-contacting applications. The influence of surfaces on the activation a ...[more]

PMID: 30551688

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Project description:Essentials The mechanism for the auto-inhibition of von Willebrand factor (VWF) remains unclear. Hydrogen exchange of two VWF A1 fragments with disparate activities was measured and compared. Discontinuous residues flanking A1 form a structural module that blocks A1 binding to the platelet. Our results suggest a potentially unified model of VWF activation. Click to hear an ISTH Academy presentation on the domain architecture of VWF and activation by elongational flow by Dr Springer SUMMARY: Background How von Willebrand factor (VWF) senses and responds to shear flow remains unclear. In the absence of shear flow, VWF or its fragments can be induced to bind spontaneously to platelet GPIb?. Objectives To elucidate the auto-inhibition mechanism of VWF. Methods Hydrogen-deuterium exchange (HDX) of two recombinant VWF fragments expressed from baby hamster kidney cells were measured and compared. Results The shortA1 protein contains VWF residues 1261-1472 and binds GPIb? with a significantly higher affinity than the longA1 protein that contains VWF residues 1238-1472. Both proteins contain the VWF A1 domain (residues 1272-1458). Many residues in longA1, particularly those in the N- and C-terminal sequences flanking the A1 domain, and in helix ?1, loops ?1?2 and ?3?2, demonstrated markedly reduced HDX compared with their counterparts in shortA1. The HDX-protected region in longA1 overlaps with the GPIb?-binding interface and is clustered with type 2B von Willebrand disease (VWD) mutations. Additional comparison with the HDX of denatured longA1 and ristocetin-bound longA1 indicates the N- and C-terminal sequences flanking the A1 domain form cooperatively an integrated autoinhibitory module (AIM) that interacts with the HDX-protected region. Binding of ristocetin to the C-terminal part of the AIM desorbs the AIM from A1 and enables longA1 binding to GPIb?. Conclusion The discontinuous AIM binds the A1 domain and prevents it from binding to GPIb?, which has significant implications for the pathogenesis of type 2B VWD and the shear-induced activation of VWF activity.

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Structure of von Willebrand factor A1 on polystyrene determined from experimental and calculated sum frequency generation spectra.

Publications

Structure of von Willebrand factor A1 on polystyrene determined from experimental and calculated sum frequency generation spectra.

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