skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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 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 » 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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 8 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Changes in Thermodynamic Stability of von Willebrand Factor Differentially Affect the Force-Dependent Binding to Platelet GPIbα
journal, July 2009


Structures of Glycoprotein Ibalpha and Its Complex with von Willebrand Factor A1 Domain
journal, August 2002


Von Willebrand factor-A1 domain binds platelet glycoprotein Ibα in multiple states with distinctive force-dependent dissociation kinetics
journal, September 2015


Genetic Variants of von Willebrand's Disease
journal, August 1972


The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation
journal, January 2005

  • Fukuda, Koichi; Doggett, Teresa; Laurenzi, Ian J.
  • Nature Structural & Molecular Biology, Vol. 12, Issue 2
  • DOI: 10.1038/nsmb892

Overview of the CCP 4 suite and current developments
journal, March 2011

  • Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S0907444910045749

A molten globule intermediate of the Von Willebrand factor A1 domain firmly tethers platelets under shear flow: Platelet Adhesion to Molten Globule Conformation
journal, November 2013

  • Tischer, Alexander; Madde, Pranathi; Blancas-Mejia, Luis. M.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 82, Issue 5
  • DOI: 10.1002/prot.24464

Adjustment of conformational flexibility is a key event in the thermal adaptation of proteins
journal, June 1998

  • Zavodszky, P.; Kardos, J.; Svingor, A.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 13
  • DOI: 10.1073/pnas.95.13.7406

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
  • DOI: 10.1107/S0907444904019158

Activation of Adenylate Kinase by Denaturants Is Due to the Increasing Conformational Flexibility at Its Active Sites
journal, September 1997

  • Zhang, Hong-Jie; Sheng, Xiang-Rong; Pan, Xian-Ming
  • Biochemical and Biophysical Research Communications, Vol. 238, Issue 2
  • DOI: 10.1006/bbrc.1997.7301

Structural Basis of Regulation of von Willebrand Factor Binding to Glycoprotein Ib
journal, January 2014

  • Blenner, Mark A.; Dong, Xianchi; Springer, Timothy A.
  • Journal of Biological Chemistry, Vol. 289, Issue 9
  • DOI: 10.1074/jbc.M113.511220

Crystal Structure of the von Willebrand Factor A1 Domain and Implications for the Binding of Platelet Glycoprotein Ib
journal, April 1998

  • Emsley, Jonas; Cruz, Miguel; Handin, Robert
  • Journal of Biological Chemistry, Vol. 273, Issue 17
  • DOI: 10.1074/jbc.273.17.10396

Von Willebrand's Disease Type B: A Newly Defined Bleeding Diathesis
journal, June 1973


Towards automated crystallographic structure refinement with phenix.refine
journal, March 2012

  • Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel
  • Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4
  • DOI: 10.1107/S0907444912001308

Crystal structure of the von Willebrand factor A1 domain in complex with the function blocking NMC-4 Fab
journal, March 1998

  • Celikel, Reha; Varughese, Kottayil I.
  • Nature Structural Biology, Vol. 5, Issue 3
  • DOI: 10.1038/nsb0398-189

Quantitative Assay of a Plasma Factor Deficient in von Willebrand's Disease that is Necessary for Platelet Aggregation. RELATIONSHIP TO FACTOR VIII PROCOAGULANT ACTIVITY AND ANTIGEN CONTENT
journal, November 1973

  • Weiss, Harvey J.; Hoyer, Leon W.; Rickles, Frederick R.
  • Journal of Clinical Investigation, Vol. 52, Issue 11
  • DOI: 10.1172/JCI107465

Structural Basis of von Willebrand Factor Activation by the Snake Toxin Botrocetin
journal, July 2002


Crystal Structure of the Wild-type von Willebrand Factor A1-Glycoprotein Ibα Complex Reveals Conformation Differences with a Complex Bearing von Willebrand Disease Mutations
journal, March 2004

  • Dumas, John J.; Kumar, Ravindra; McDonagh, Thomas
  • Journal of Biological Chemistry, Vol. 279, Issue 22
  • DOI: 10.1074/jbc.M401659200

Enzyme flexibility and enzyme action
journal, December 1959

  • Koshland, D. E.
  • Journal of Cellular and Comparative Physiology, Vol. 54, Issue S1
  • DOI: 10.1002/jcp.1030540420

Hot spots in cold adaptation: Localized increases in conformational flexibility in lactate dehydrogenase A4 orthologs of Antarctic notothenioid fishes
journal, September 1998

  • Fields, P. A.; Somero, G. N.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 19
  • DOI: 10.1073/pnas.95.19.11476

Misfolding of vWF to Pathologically Disordered Conformations Impacts the Severity of von Willebrand Disease
journal, September 2014

  • Tischer, Alexander; Madde, Pranathi; Moon-Tasson, Laurie
  • Biophysical Journal, Vol. 107, Issue 5
  • DOI: 10.1016/j.bpj.2014.07.026

von Willebrand factor A1 domain can adequately substitute for A3 domain in recruitment of flowing platelets to collagen
journal, October 2006


Rational modulation of conformational fluctuations in adenylate kinase reveals a local unfolding mechanism for allostery and functional adaptation in proteins
journal, September 2009

  • Schrank, T. P.; Bolen, D. W.; Hilser, V. J.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 40
  • DOI: 10.1073/pnas.0906510106

Shear stress and the role of high molecular weight von Willebrand factor multimers in thrombus formation
journal, January 2005


Shear-induced unfolding triggers adhesion of von Willebrand factor fibers
journal, April 2007

  • Schneider, S. W.; Nuschele, S.; Wixforth, A.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 19
  • DOI: 10.1073/pnas.0608422104

von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib.
journal, October 1992

  • Rabinowitz, I.; Tuley, E. A.; Mancuso, D. J.
  • Proceedings of the National Academy of Sciences, Vol. 89, Issue 20
  • DOI: 10.1073/pnas.89.20.9846

Structural Origins of Misfolding Propensity in the Platelet Adhesive Von Willebrand Factor A1 Domain
journal, July 2015

  • Zimmermann, Michael T.; Tischer, Alexander; Whitten, Steven T.
  • Biophysical Journal, Vol. 109, Issue 2
  • DOI: 10.1016/j.bpj.2015.06.008

A Structural Explanation for the Antithrombotic Activity of ARC1172, a DNA Aptamer that Binds von Willebrand Factor Domain A1
journal, November 2009


Conformational Stability and Domain Unfolding of the Von Willebrand Factor A Domains
journal, February 2007

  • Auton, Matthew; Cruz, Miguel A.; Moake, Joel
  • Journal of Molecular Biology, Vol. 366, Issue 3
  • DOI: 10.1016/j.jmb.2006.10.067

Better models by discarding data?
journal, June 2013

  • Diederichs, K.; Karplus, P. A.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7
  • DOI: 10.1107/S0907444913001121

Identification of a New Type 2M von Willebrand Disease Mutation also at Position 1324 of von Willebrand Factor
journal, January 2002

  • Hilbert, L.; Fressinaud, E.; Ribba, A. S.
  • Thrombosis and Haemostasis, Vol. 87, Issue 04
  • DOI: 10.1055/s-0037-1613060

    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
    • Journal of Thrombosis and Haemostasis, Vol. 17, Issue 12
    • DOI: 10.1111/jth.14597

    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
    • Journal of Thrombosis and Haemostasis, Vol. 17, Issue 12
    • DOI: 10.1111/jth.14597