Gain-of-Function Variant p.Pro2555Arg of von Willebrand Factor Increases Aggregate
Size through Altering Stem Dynamics
von Willebrand factor (VWF) contains functionally critical domains which have been
extensively studied in hemostasis and bleeding via molecular and genetic approaches.
Flow-based assays have unraveled the importance of the A1A2A3 cluster for VWF function
and have validated loss-of-function and gain-of-function VWF variants.[1] Various VWF mutations causing deficient shear stress-regulated unfolding of this
cluster showed the importance of the three-dimensional interaction of the VWF A1 domain
with its platelet receptor, the glycoprotein Ib (GPIb) complex. Recently, Schneppenheim
et al clarified why the common p.Phe2561Tyr VWF variant displays prothrombotic properties
at low shear stress, due to a mutation in the VWF C4 domain.[2] In the absence of flow, the mutated domain binds normally to platelet αIIbβ3 via
its RGD sequence, the prothrombotic properties of p.Phe2561Tyr VWF being elicited
only in response to shear stress. In this issue, Huck et al further elucidated this
mechanism, via an elegant study of p.Pro2555Arg VWF, which shear-dependently doubled
platelet aggregate size during Cone and Plate aggregometry.[3] The underlying mutation again impacted on dimeric VWF C4 domain interactions with
αIIbβ3, via a mechanism dictated by more sensitive opening of the zipped VWF stem
under increasing shear forces, allowing more pronounced binding of p.Pro2555Arg VWF
to αIIbβ3, which in turn increased platelet aggregate formation. Extensive biochemical
and biophysical study of p.Pro2555Arg VWF indeed demonstrated mutant-induced modifications
in the dimeric structure of the C-terminal region, triggering increased flexibility
in the stem region. Defective VWF function can be compensated for by fibrinogen (fg),
but elegant shear stress-dependent assays in the absence or presence of fg and αIIbβ3
neutralization experiments defined the prothrombotic properties for p.Pro2555Arg VWF
as a gain-of-function mutant, requiring flow to become operational.[3] In addition to earlier mutations affecting k
on and k
off for VWF A1–GPIbα interactions, this interesting study identifies the VWF C4 domain
as a new source of clinically relevant VWF variants.
