A biophysical view on von Willebrand factor activation

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 -