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Title: 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 His 1322 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 probabilitymore » of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [3];  [2];  [1]
  1. Mayo Clinic, Rochester, MN (United States)
  2. Baylor College of Medicine, Houston, TX (United States)
  3. 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) (SC-22)
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. doi: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. doi: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 = {2015},
month = {12}
}

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Works referenced in this record:

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
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