Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor
Abstract
Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limited proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The better stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His1322 across the β2-β3 hairpin in the GPIbα binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIbα binding interface of normal VWF enhances the probability ofmore »
- Authors:
-
- Mayo Clinic, Rochester, MN (United States)
- Baylor College of Medicine, Houston, TX (United States)
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1379101
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 291; Journal Issue: 8; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Tischer, Alexander, Campbell, James C., Machha, Venkata R., Moon-Tasson, Laurie, Benson, Linda M., Sankaran, Banumathi, Kim, Choel, and Auton, Matthew. Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor. United States: N. p., 2015.
Web. doi:10.1074/jbc.M115.703850.
Tischer, Alexander, Campbell, James C., Machha, Venkata R., Moon-Tasson, Laurie, Benson, Linda M., Sankaran, Banumathi, Kim, Choel, & Auton, Matthew. Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor. United States. https://doi.org/10.1074/jbc.M115.703850
Tischer, Alexander, Campbell, James C., Machha, Venkata R., Moon-Tasson, Laurie, Benson, Linda M., Sankaran, Banumathi, Kim, Choel, and Auton, Matthew. Wed .
"Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor". United States. https://doi.org/10.1074/jbc.M115.703850. https://www.osti.gov/servlets/purl/1379101.
@article{osti_1379101,
title = {Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor},
author = {Tischer, Alexander and Campbell, James C. and Machha, Venkata R. and Moon-Tasson, Laurie and Benson, Linda M. and Sankaran, Banumathi and Kim, Choel and Auton, Matthew},
abstractNote = {Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limited proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The better stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His1322 across the β2-β3 hairpin in the GPIbα binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIbα binding interface of normal VWF enhances the probability of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure.},
doi = {10.1074/jbc.M115.703850},
journal = {Journal of Biological Chemistry},
number = 8,
volume = 291,
place = {United States},
year = {Wed Dec 16 00:00:00 EST 2015},
month = {Wed Dec 16 00:00:00 EST 2015}
}
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Works referencing / citing this record:
Platelet‐type von Willebrand disease: Local disorder of the platelet GPI bα β‐switch drives high‐affinity binding to von Willebrand factor
journal, September 2019
- Tischer, Alexander; Machha, Venkata R.; Moon‐Tasson, Laurie
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Delimiting the autoinhibitory module of von Willebrand factor
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Glycosylation sterically inhibits platelet adhesion to von Willebrand factor without altering intrinsic conformational dynamics
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