Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module

Autor: Emily R. Legan, Emma-Ruoqi Xu, Michael C. Berndt, Nicholas A Arce, Jonas Emsley, Alexander K. Brown, Wenpeng Cao, Renhao Li, Moriah Simone Wilson, X. Frank Zhang
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Models
Molecular
congenital
hereditary
and neonatal diseases and abnormalities
Platelet Aggregation
Protein Conformation
Science
Shear force
General Physics and Astronomy
030204 cardiovascular system & hematology
In Vitro Techniques
Crystallography
X-Ray
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
0302 clinical medicine
Von Willebrand factor
Single-molecule biophysics
Protein Domains
Tensile Strength
hemic and lymphatic diseases
von Willebrand Factor
Humans
Platelet
Protein Unfolding
Multidisciplinary
biology
Chemistry
Blood proteins
Protein Stability
Antibodies
Monoclonal
General Chemistry
Single-Domain Antibodies
Single Molecule Imaging
Biomechanical Phenomena
030104 developmental biology
Ristocetin
Hemostasis
Mutation
Biophysics
biology.protein
cardiovascular system
Caplacizumab
circulatory and respiratory physiology
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature Communications
ISSN: 2041-1723
Popis: Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX complex. Here we show that the shear-responsive element controlling VWF activation resides in the discontinuous autoinhibitory module (AIM) flanking A1. Application of tensile force in a single-molecule setting induces cooperative unfolding of the AIM to expose A1. The AIM-unfolding force is lowered by truncating either N- or C-terminal AIM region, type 2B VWD mutations, or binding of a ristocetin-mimicking monoclonal antibody, all of which could activate A1. Furthermore, the AIM is mechanically stabilized by the nanobody that comprises caplacizumab, the only FDA-approved anti-thrombotic drug to-date that targets VWF. Thus, the AIM is a mechano-regulator of VWF activity. Its conformational dynamics may define the extent of VWF autoinhibition and subsequent activation under force.
Von Willebrand factor (VWF) is a large glycoprotein in the blood secreted from endothelial cells lining the blood vessel and activation of VWF leads to formation of VWF-platelet complexes or thrombi. Here authors use single-molecule force measurement, X-ray crystallography and functional measurements to monitor the activation of VWF via mechanical unfolding of the autoinhibitory module (AIM).
Databáze: OpenAIRE
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