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Title: Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor

Journal Article · · Journal of Biological Chemistry
 [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)
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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.

Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1379101
Journal Information:
Journal of Biological Chemistry, Vol. 291, Issue 8; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 17 works
Citation information provided by
Web of Science

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Cited By (3)

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
Delimiting the autoinhibitory module of von Willebrand factor journal August 2018
Glycosylation sterically inhibits platelet adhesion to von Willebrand factor without altering intrinsic conformational dynamics journal October 2019

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