A biophysical view on von Willebrand factor activation
Standard
A biophysical view on von Willebrand factor activation. / Löf, Achim; Müller, Jochen P; Brehm, Maria A.
In: J CELL PHYSIOL, Vol. 233, No. 2, 02.2018, p. 799-810.Research output: SCORING: Contribution to journal › SCORING: Review article › Research
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - A biophysical view on von Willebrand factor activation
AU - Löf, Achim
AU - Müller, Jochen P
AU - Brehm, Maria A
N1 - © 2017 Wiley Periodicals, Inc.
PY - 2018/2
Y1 - 2018/2
N2 - The process of hemostatic plug formation at sites of vascular injury crucially relies on the large multimeric plasma glycoprotein von Willebrand factor (VWF) and its ability to recruit platelets to the damaged vessel wall via interaction of its A1 domain with platelet GPIbα. Under normal blood flow conditions, VWF multimers exhibit a very low binding affinity for platelets. Only when subjected to increased hydrodynamic forces, which primarily occur in connection with vascular injury, VWF can efficiently bind to platelets. This force-regulation of VWF's hemostatic activity is not only highly intriguing from a biophysical perspective, but also of eminent physiological importance. On the one hand, it prevents undesired activity of VWF in intact vessels that could lead to thromboembolic complications and on the other hand, it enables efficient VWF-mediated platelet aggregation exactly where needed. Here, we review recent studies that mainly employed biophysical approaches in order to elucidate the molecular mechanisms underlying the complex mechano-regulation of the VWF-GPIbα interaction. Their results led to two main hypotheses: first, intramolecular shielding of the A1 domain is lifted upon force-induced elongation of VWF; second, force-induced conformational changes of A1 convert it from a low-affinity to a high-affinity state. We critically discuss these hypotheses and aim at bridging the gap between the large-scale behavior of VWF as a linear polymer in hydrodynamic flow and the detailed properties of the A1-GPIbα bond at the single-molecule level.
AB - The process of hemostatic plug formation at sites of vascular injury crucially relies on the large multimeric plasma glycoprotein von Willebrand factor (VWF) and its ability to recruit platelets to the damaged vessel wall via interaction of its A1 domain with platelet GPIbα. Under normal blood flow conditions, VWF multimers exhibit a very low binding affinity for platelets. Only when subjected to increased hydrodynamic forces, which primarily occur in connection with vascular injury, VWF can efficiently bind to platelets. This force-regulation of VWF's hemostatic activity is not only highly intriguing from a biophysical perspective, but also of eminent physiological importance. On the one hand, it prevents undesired activity of VWF in intact vessels that could lead to thromboembolic complications and on the other hand, it enables efficient VWF-mediated platelet aggregation exactly where needed. Here, we review recent studies that mainly employed biophysical approaches in order to elucidate the molecular mechanisms underlying the complex mechano-regulation of the VWF-GPIbα interaction. Their results led to two main hypotheses: first, intramolecular shielding of the A1 domain is lifted upon force-induced elongation of VWF; second, force-induced conformational changes of A1 convert it from a low-affinity to a high-affinity state. We critically discuss these hypotheses and aim at bridging the gap between the large-scale behavior of VWF as a linear polymer in hydrodynamic flow and the detailed properties of the A1-GPIbα bond at the single-molecule level.
KW - Animals
KW - Blood Platelets
KW - Hemostasis
KW - Humans
KW - Hydrodynamics
KW - Mechanotransduction, Cellular
KW - Platelet Activation
KW - Platelet Aggregation
KW - Platelet Glycoprotein GPIb-IX Complex
KW - Protein Binding
KW - Protein Interaction Domains and Motifs
KW - Structure-Activity Relationship
KW - von Willebrand Factor
KW - Journal Article
KW - Review
U2 - 10.1002/jcp.25887
DO - 10.1002/jcp.25887
M3 - SCORING: Review article
C2 - 28256724
VL - 233
SP - 799
EP - 810
JO - J CELL PHYSIOL
JF - J CELL PHYSIOL
SN - 0021-9541
IS - 2
ER -