A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

Yee, Andrew; Gildersleeve, Robert; Gu, Shufang; Kretz, Colin A.; McGee, Beth; Carr, Keisha M.; Pipe, Steven W.; Ginsburg, David

doi:10.1182/blood-2013-11-540534

Cited by 64 publications

(65 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several phase 1/2 studies are underway, and preliminary analyses have shown that ricolinostat has clinical activity in patients with RRMM when combined with bortezomib and low-dose dexamethasone [70], lenalidomide and dexamethasone [71], and pomalidomide and dexamethasone [72]. Additionally, its selective HDAC6 inhibition is expected to result in increased tolerability.…”

Section: Treatment Of Rrmm In Europe: the Current Therapeutic Landscapementioning

confidence: 99%

The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective

2016

View full text Add to dashboard Cite

Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe. Funding: Editorial support, funded by Novartis Pharmaceuticals.

show abstract

Section: Treatment Of Rrmm In Europe: the Current Therapeutic Landscapementioning

confidence: 99%

The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective

2016

View full text Add to dashboard Cite

show abstract

“…6 We and others have previously reported that VWF fragments are sufficient to bind FVIII and that propeptide processing of these VWF fragments enhances the affinity for FVIII. [7][8][9] Several of these VWF fragments were also sufficient to elevate FVIII levels in VWF-deficient mice. 7 To further explore the association between VWF and FVIII, we used single-particle negative-stain electron microscopy (EM) to characterize the architecture of dimeric VWF D9D3 domains ([D9D3] 2 ) alone and in complex with FVIII.…”

Section: Introductionmentioning

confidence: 98%

Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII

Yee¹,

Oleskie²,

Dosey³

et al. 2015

Blood

Self Cite

View full text Add to dashboard Cite

• The VWF D9 domains are flexibly tethered entities projecting outside antiparallel dimers of the VWF D3 domain. • Extensive interactionsbetween the VWF D9 domain and primarily the FVIII C1 domain mediate VWF-FVIII association.Binding to the von Willebrand factor (VWF) D9D3 domains protects factor VIII (FVIII) from rapid clearance. We performed single-particle electron microscopy (EM) analysis of negatively stained specimens to examine the architecture of D9D3 alone and in complex with FVIII. The D9D3 dimer ([D9D3] 2 ) comprises 2 antiparallel D3 monomers with flexibly attached protrusions of D9. FVIII-VWF association is primarily established between the FVIII C1 domain and the VWF D9 domain, whereas weaker interactions appear to be mediated between both FVIII C domains and the VWF D3 core. IntroductionThe strong association of plasma factor VIII (FVIII) with circulating von Willebrand factor (VWF) secures FVIII from rapid clearance in the blood. The VWF-FVIII complex forms through a high-affinity interaction between the FVIII light chain and the VWF D9D3 domains. 1Mutations within VWF that abrogate or abolish this high-affinity binding lead to type 2N von Willebrand disease, a condition characterized by reduced plasma levels of FVIII. 2The tertiary structure of mature VWF, particularly at the N-terminal D9D3 domains, regulates the affinity for FVIII. VWF circulates as a multi-subunit protein comprising repeated domains that distinctly facilitate VWF packaging and hemostasis.3 The VWF propeptide (domains D1and D2) catalyzes the multimerization of VWF via intermolecular disulfide bonds at the D3 domain ( Figure 1A). 4 In the absence of propeptide-dependent posttranslational modifications to the D9D3 domains, VWF binds FVIII with reduced affinity.5 Cleavage of the propeptide by furin facilitates FVIII stabilization in the circulation. 6 We and others have previously reported that VWF fragments are sufficient to bind FVIII and that propeptide processing of these VWF fragments enhances the affinity for FVIII.7-9 Several of these VWF fragments were also sufficient to elevate FVIII levels in VWF-deficient mice. 7To further explore the association between VWF and FVIII, we used single-particle negative-stain electron microscopy (EM) to characterize the architecture of dimeric VWF D9D3 domains ([D9D3] 2 ) alone and in complex with FVIII. Study designProtein expression, purification, and analyses are detailed in supplemental Data available on the Blood Web site. The online version of this article contains a data supplement. Results and discussionThere is an Inside Blood Commentary on this article in this issue.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. , each monomer appears as an ovoid density along the dimer symmetry axis accompanied by a weaker elongated density, which we term the "handle," in the periphery. The dimensions of the handle are ;20Å ...

show abstract

“…5,6 Consistent with these findings, recombinant D9D3 domains have been shown to be sufficient to elevate levels of endogenous FVIII in VWF-deficient mice. 7 The reciprocal binding site for VWF on FVIII was initially localized broadly to its light chain. 8 Subsequent studies demonstrated that the a3 acidic peptide region (E1649-R1689) 9 and a restricted fragment thereof (K1673-R1689), 10 as well as sulfation on residue Y1680 within this region, are important for VWF binding.…”

Section: Introductionmentioning

confidence: 99%

Mapping the interaction between factor VIII and von Willebrand factor by electron microscopy and mass spectrometry

Chiu

Bou-Assaf

Chhabra

et al. 2015

Blood

View full text Add to dashboard Cite

Key Points• Electron microscopy and hydrogen-deuterium exchange establish the C1 domain as the major binding site for the VWF D9D3 domain on FVIII.• Additional sites implicated in the FVIII-VWF interaction are located within the a3 acidic peptide and the A3 and C2 domains of FVIII.Association with the D9D3 domain of von Willebrand factor (VWF) stabilizes factor VIII (FVIII) in the circulation and maintains it at a level sufficient to prevent spontaneous bleeding. We used negative-stain electron microscopy (EM) to visualize complexes of FVIII with dimeric and monomeric forms of the D9D3 domain. The EM averages show that FVIII interacts with the D9D3 domain primarily through its C1 domain, with the C2 domain providing a secondary attachment site. Hydrogen-deuterium exchange mass spectrometry corroborated the importance of the C1 domain in D9D3 binding and implicates additional surface regions on FVIII in the interaction. Together, our results establish that the C1 domain is the major binding site on FVIII for VWF, reiterate the importance of the a3 acidic peptide in VWF binding, and suggest that the A3 and C2 domains play ancillary roles in this interaction. (Blood. 2015;126(8):935-938)

show abstract

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

Cited by 64 publications

References 55 publications

The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective

The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective

Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII

Mapping the interaction between factor VIII and von Willebrand factor by electron microscopy and mass spectrometry

Contact Info

Product

Resources

About