PMID: 28279966

 

    Legend: Gene, Sites

Title : Plasmin Cleaves Von Willebrand Factor at K1491-R1492 in the A1-A2 Linker Region in a Shear- and Glycan-Dependent Manner In Vitro

Abstract :
  1. Previous studies have demonstrated a role for plasmin in regulating plasma von Willebrand factor ( VWF ) multimer com position
  2. Moreover, emerging data have shown that plasmin-induced cleavage of VWF is of particular importance in specific pathological states
  3. Interestingly, plasmin has been successfully used as an alternative to ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif ) in a mouse model of thrombotic thrombocytopenic purpura
  4. Consequently, elucidating the molecular mechanisms through which plasmin binds and cleaves VWF is not only of basic scientific interest but also of direct clinical importance
  5. Our aim was to investigate factors that modulate the susceptibility of human VWF to proteolysis by plasmin
  6. We have adapted the VWF vortex proteolysis assay to allow for time-dependent shear exposure studies
  7. We show that globular VWF is resistant to plasmin cleavage under static conditions, but is readily cleaved by plasmin under shear
  8. Although both plasmin and ADAMTS13 cleave VWF in a shear-dependent manner, plasmin does not cleave at the Tyr1605-Met1606 ADAMTS13 proteolytic site in the A2 domain
  9. Rather under shear stress conditions, or in the presence of denaturants, such as urea or ristocetin, plasmin cleaves the K1491-R1492 peptide bond within the VWF A1-A2 linker region
  10. Finally, we demonstrate that VWF susceptibility to plasmin proteolysis at K1491-R1492 is modulated by local N-linked glycan expression within A1A2A3, and specifically inhibited by heparin binding to the A1 domain
  11. Improved understanding of the plasmin- VWF interaction offers exciting opportunities to develop novel adjunctive therapies for the treatment of refractory thrombotic thrombocytopenic purpura
Output (sent_index, trigger, protein, sugar, site):
Output(Part-Of) (sent_index, protein, site):
  • 0. Plasmin Cleaves Von Willebrand Factor, -
  • 0. Plasmin Cleaves Von Willebrand Factor, K1491-R1492
  • 1. von Willebrand factor, position
  • 10. A1, domain
  • 3. disintegrin, motif
  • 3. metalloproteinase, motif
  • 3. thrombospondin type 1, motif
  • 8. Tyr1605-Met1606 ADAMTS13, site
  • 9. VWF, region
*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

 

Protein NCBI ID SENTENCE INDEX
von Willebrand factor 7450 1
Plasmin Cleaves Von Willebrand Factor 5340 0
Tyr1605-Met1606 ADAMTS13 11093 8
ADAMTS13 279028 3,8
VWF 7450 1,2,4,5,6,7,8,9,10,11
Interestingly, plasmin 5340 3
plasmin 5340 1,2,4,5,7,8,9,10,11