scholarly journals The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity

2015 ◽  
Vol 43 (5) ◽  
pp. 795-800 ◽  
Author(s):  
Helen Troilo ◽  
Anne L. Barrett ◽  
Alexander P. Wohl ◽  
Thomas A. Jowitt ◽  
Richard F. Collins ◽  
...  
Keyword(s):  
Surface Receptors ◽  
Twisted Gastrulation ◽  
C Terminus ◽  
Morphogenetic Protein ◽  
Recent Developments ◽  
Factor Type ◽  
Bmp Signalling ◽  
Related Proteins ◽  
Von Willebrand ◽  
Willebrand Factor

Chordin-mediated regulation of bone morphogenetic protein (BMP) family growth factors is essential in early embryogenesis and adult homoeostasis. Chordin binds to BMPs through cysteine-rich von Willebrand factor type C (vWC) homology domains and blocks them from interacting with their cell surface receptors. These domains also self-associate and enable chordin to target related proteins to fine-tune BMP regulation. The chordin–BMP inhibitory complex is strengthened by the secreted glycoprotein twisted gastrulation (Tsg); however, inhibition is relieved by cleavage of chordin at two specific sites by tolloid family metalloproteases. As Tsg enhances this cleavage process, it serves a dual role as both promoter and inhibitor of BMP signalling. Recent developments in chordin research suggest that rather than simply being by-products, the cleavage fragments of chordin continue to play a role in BMP regulation. In particular, chordin cleavage at the C-terminus potentiates its anti-BMP activity in a type-specific manner.

scholarly journals Molecular Characterization of the Von Willebrand Factor Type D Domain of Vitellogenin from Takifugu flavidus

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 181
Author(s):  
Kun Qiao ◽  
Caiyun Jiang ◽  
Min Xu ◽  
Bei Chen ◽  
Wenhui Qiu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Von Willebrand Factor ◽  
Molecular Mechanisms ◽  
Protein Domain ◽  
Type D ◽  
Protein Toxin ◽  
Factor Type ◽  
Von Willebrand ◽  
Willebrand Factor

The von Willebrand factor type D (VWD) domain in vitellogenin has recently been found to bind tetrodotoxin. The way in which this protein domain associates with tetrodotoxin and participates in transporting tetrodotoxin in vivo remains unclear. A cDNA fragment of the vitellogenin gene containing the VWD domain from pufferfish (Takifugu flavidus) (TfVWD) was cloned. Using in silico structural and docking analyses of the predicted protein, we determined that key amino acids (namely, Val115, ASP116, Val117, and Lys122) in TfVWD mediate its binding to tetrodotoxin, which was supported by in vitro surface plasmon resonance analysis. Moreover, incubating recombinant rTfVWD together with tetrodotoxin attenuated its toxicity in vivo, further supporting protein–toxin binding and indicating associated toxicity-neutralizing effects. Finally, the expression profiling of TfVWD across different tissues and developmental stages indicated that its distribution patterns mirrored those of tetrodotoxin, suggesting that TfVWD may be involved in tetrodotoxin transport in pufferfish. For the first time, this study reveals the amino acids that mediate the binding of TfVWD to tetrodotoxin and provides a basis for further exploration of the molecular mechanisms underlying the enrichment and transfer of tetrodotoxin in pufferfish.

Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 425-436 ◽  
Author(s):  
Hong Yang ◽  
Sean Lang ◽  
Zhimin Zhai ◽  
Ling Li ◽  
Walter H. A. Kahr ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Human Fibrinogen ◽  
C Terminus ◽  
Β3 Integrin ◽  
Von Willebrand ◽  
Selectin Binding ◽  
Willebrand Factor ◽  
Deficient Mice ◽  
Granule Release

Abstract Platelet P-selectin plays important roles in inflammation and contributes to thrombosis and hemostasis. Although it has been reported that von Willebrand factor (VWF) affects P-selectin expression on endothelial cells, little information is available regarding regulation of platelet P-selectin expression. Here, we first observed that P-selectin expression was significantly decreased on platelets of fibrinogen and VWF double-deficient mice. Subsequently, we identified this was due to fibrinogen deficiency. Impaired P-selectin expression on fibrinogen-deficient platelets was further confirmed in human hypofibrinogenemic patients. We demonstrated that this impairment is unlikely due to excessive P-selectin shedding, deficient fibrinogen-mediated cell surface P-selectin binding, or impaired platelet granule release, but rather is due to decreased platelet P-selectin content. Fibrinogen transfusion completely recovered this impairment in fibrinogen-deficient (Fg−/−) mice, and engagement of the C-terminus of the fibrinogen γ chain with β3 integrin was required for this process. Furthermore, Fg−/− platelets significantly increased P-selectin expression following transfusion into β3 integrin–deficient mice and when cultured with fibrinogen. These data suggest fibrinogen may play important roles in inflammation, thrombosis, and hemostasis via enhancement of platelet P-selectin expression. Since human fibrinogen levels vary significantly in normal and diseased populations, P-selectin as an activation marker on platelets should be used with caution.

Platelet-collagen interaction: is GPVI the central receptor?

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 449-461 ◽  
Author(s):  
Bernhard Nieswandt ◽  
Steve P. Watson
Keyword(s):  
Adenosine Diphosphate ◽  
Mouse Strains ◽  
Central Position ◽  
Complex Processes ◽  
Collagen Receptors ◽  
Step Model ◽  
Recent Developments ◽  
Von Willebrand ◽  
Second Wave ◽  
Willebrand Factor

AbstractAt sites of vascular injury, platelets come into contact with subendothelial collagen, which triggers their activation and the formation of a hemostatic plug. Besides glycoprotein Ib (GPIb) and αIIbβ3 integrin, which indirectly interact with collagen via von Willebrand factor (VWF), several collagen receptors have been identified on platelets, most notably α2β1 integrin and the immunoglobulin (Ig) superfamily member GPVI. Within the last few years, major advances have been made in understanding platelet-collagen interactions including the molecular cloning of GPVI, the generation of mouse strains lacking individual collagen receptors, and the development of collagen receptor–specific antibodies and synthetic peptides. It is now recognized that platelet adhesion to collagen requires prior activation of integrins through “inside-out” signals generated by GPVI and reinforced by released second-wave mediators adenosine diphosphate (ADP) and thromboxane A2. These developments have led to revision of the original “2-site, 2-step” model, which now places GPVI in a central position in the complex processes of platelet tethering, activation, adhesion, aggregation, degranulation, and procoagulant activity on collagen. This review discusses these recent developments and proposes possible mechanisms for how GPVI acts in concert with other receptors and signaling pathways to initiate hemostasis and arterial thrombosis.

Regulation of Von Willebrand Factor A1 Domain by Mechanical Force and Neighboring Domains

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2117-2117
Author(s):  
Wendy E Thomas ◽  
Rebecca A Penkala ◽  
Elaine Hillenmeyer ◽  
Matthew Whitfield ◽  
An-yue Tu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Shear Stress ◽  
Von Willebrand Factor ◽  
Mechanical Force ◽  
Platelet Glycoprotein ◽  
Bond Rupture ◽  
C Terminus ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 2117 Regulation of the bond between platelet glycoprotein (GP) Ibα of the GPIb-IX-V complex, and the von Willebrand Factor (VWF) A1 domain is critical to the balance between hemostasis and thrombosis, particularly in high shear conditions. The GPIbα-A1 interaction is known to be activated by shear stress and inhibited by neighboring domains in VWF, but the role of neighboring domains in the shear-dependence remained unknown. Here it is shown that platelet aggregation required shear stress in the presence of VWF proteins that contain the neighboring D′D3 domain (Plus D′D3 or plasma VWF) but that platelets aggregate spontaneously with a protein that lacks this region (Delta D′D3). Moreover, platelets and microspheres coated with the N-terminal 300 amino acids of GPIbα (GC300) bind to immobilized VWF in a shear-enhanced manner for Plus D′D3 but not for Delta D′D3. In single-molecule force spectroscopy experiments, the D′D3 domain decreased the number of GPIbα-A1 bonds that formed, but did not alter bond rupture force, consistent with the hypothesis that D′D3 shields the A1 domain. By expressing recombinant VWF fragments that contain the A1 domain and various lengths of the N-terminal region, we determined that most of the inhibition by the D′D3 domain was conferred by 23 amino acids in the linker between the A1 domain and the D′D3 domain. By anchoring the fragments to the surface in an oriented manner, we demonstrated that binding was much stronger when force was applied between GPIbα and the A1 C-terminus, than when force was applied between GPIbα and the A1 N-terminus, similar to what has been observed for integrins. Based on these results, we propose the following model for regulation of VWF by mechanical force. When multimeric VWF is stretched in flow, the D′D3 domains are pulled away from the A1 domains, exposing the latter to bind platelets. When force is applied between GPIbα and the C-terminus of A1, it induces an activating conformational change that could be analogous to that seen in integrins. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance

2015 ◽  
Vol 13 (5) ◽  
pp. 815-820 ◽  
Author(s):  
N. Wohner ◽  
P. Legendre ◽  
C. Casari ◽  
O. D. Christophe ◽  
P. J. Lenting ◽  
...  
Keyword(s):  
Shear Stress ◽  
Von Willebrand Factor ◽  
Factor Type ◽  
Von Willebrand ◽  
Willebrand Factor
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