Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor.

Leyte, Anja; Schijndel, Harm B. van; Niehrs, Christof; Huttner, Wieland B.; Verbeet, Martin Ph.; Mertens, Koen; Mourik, Jan A. van

doi:10.1016/s0021-9258(17)35234-1

Cited by 258 publications

(47 citation statements)

References 40 publications

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“…The findings demonstrated that all three antibodies completely inhibited the binding of factor VIII to immobilized VWF, and implicated that a peptide containing the fifteen amino acid residues from the Val1670-Glu1684 governed these FVIII binding reactions. The data supported the results of alternative studies suggesting that the acidic region of the amino-terminal A3 domain containing Tyr1680 was an essential region for VWF binding 12) .…”

Section: The Role Of the C2 Domain In The Fviii Light Chainsupporting

confidence: 88%

Studies on factor VIII toward a new therapeutic for hemophilia A

Shima

2021

Nihon Kessen Shiketsu Gakkaishi

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Factor VIII (FVIII) is an essential glycoprotein cofactor that accelerates the generation of factor Xa (FXa) by factor IXa (FIXa). FVIII is transformed into its active form, FVIIIa, after limited proteolytic cleavages by thrombin and FXa at the site of bleeding. My early research, using monoclonal antibodies, recombinant/synthetic polypeptides and anhydro-proteins, identified critical FVIII binding regions for von Willebrand factor (VWF), phosphatidylserine, thrombin, FXa, FIXa, APC and plasmin. The studies led to the generation of a humanized bispecific antibody to FIX(a)and FX as a new therapeutic for hemophilia A patients with and without FVIII inhibitor. The antibody, now termed emicizumab, mimics FVIIIa cofactor function by arranging FIXa and FX in a spatially suitable position, thereby accelerating FIXa-catalyzed FX activation. Phase 1 studies in healthy volunteers and in patients with hemophilia A were performed in Japan. Bleeding rates were remarkably reduced dose-dependently by weekly subcutaneous injection of the antibody irrespective of the presence FVIII inhibitor. The efficacy and tolerability and safety were further confirmed by international phase 3 studies in a total of 400 participants. Emicizumab prophylaxis has now become one of the important therapeutic options for hemophilia A with and without inhibitors

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Section: The Role Of the C2 Domain In The Fviii Light Chainsupporting

confidence: 88%

Studies on factor VIII toward a new therapeutic for hemophilia A

Shima

2021

Nihon Kessen Shiketsu Gakkaishi

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“…Usually, Ucma/GRP is γ-carboxylated at all 14 Glu residues of its amino acid chain, providing the protein with a high affinity to Ca 2+ [22]. Furthermore, Ucma/GRP is sulfated at up to two tyrosine residues, which is typical for extracellular matrix proteins, such as VDKPs or leucine-rich repeat proteoglycans, and is considered to promote protein-protein interactions [20,91,92]. In fact, we could later demonstrate that Ucma/GRP is binding to collagen type II with high affinity [26].…”

Section: Ucma/grpmentioning

confidence: 99%

Vitamin K-Dependent Proteins in Skeletal Development and Disease

Stöck

Schett

2021

IJMS

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Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.

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“…Our structure confirms the basic groove on VWF-TIL9 as the primary binding site for FVIII-a3 and underscores the biological relevance of sulfation of FVIII-Y1680 in mediating this interaction. 7,13,14,48 Similarly, the structure also provides a molecular rationale for why the VWF R816W mutation leads to the most severe form of VWD type 2N. The location of these and many other critical residues, which when mutated result in the phenotypically similar bleeding disorders of hemophilia A (FVIII) or VWD type 2N (VWF), are shown in Figure 7.…”

Section: Discussionmentioning

confidence: 99%

“…12 The role of sulfated Y1680 in FVIII-a3 has gained the most attention. 13,14 FVIII-VWF interaction is mediated by FVIII-a3 region and is severely compromised when Y1680 within FVIII-a3 is mutated or absent. Impaired FVIII-VWF interaction results in the rapid clearance of FVIII and accompanying bleeding diathesis.…”

Section: Introductionmentioning

confidence: 99%

“…Impaired FVIII-VWF interaction results in the rapid clearance of FVIII and accompanying bleeding diathesis. [14][15][16] Similarly, mutations in VWF-D9 or VWF-D3 that disrupt association with FVIII result in the bleeding disorder, von Willebrand disease (VWD) type 2N. 17,18 The FVIII-VWF interface has not yet been visualized at high resolution.…”

Section: Introductionmentioning

confidence: 99%

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Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy

Fuller

Knockenhauer

Leksa

et al. 2021

Blood

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Interaction of factor VIII (FVIII) with von Willebrand factor (VWF) is mediated by the VWF DʹD3 domains and thrombin-mediated release is essential for hemostasis after vascular injury. VWF-DʹD3 mutations resulting in loss of FVIII binding are the underlying cause of von Willebrand Disease (VWD) type 2N. Furthermore, the FVIII-VWF interaction has significant implications for the development of therapeutics for bleeding disorders, particularly hemophilia A, where endogenous VWF clearance imposes a half-life ceiling on replacement FVIII therapy. To understand the structural basis of FVIII engagement by VWF, we solved the structure of BIVV001 by cryo-electron microscopy to 2.9 Å resolution. BIVV001 is a bioengineered clinical-stage FVIII molecule for the treatment of hemophilia A. In BIVV001, VWF-DʹD3 is covalently linked to an Fc domain of a B domain-deleted recombinant FVIII (rFVIII) Fc fusion protein, resulting in a stabilized rFVIII/VWF-DʹD3 complex. Our rFVIII/VWF structure resolves BIVV001 architecture and provides a detailed spatial understanding of previous biochemical and clinical observations related to FVIII-VWF engagement. Notably, the FVIII acidic a3 peptide region (FVIII-a3), established as a critical determinant of FVIII/VWF complex formation, inserts into a basic groove formed at the VWF-Dʹ/rFVIII interface. Our structure shows direct interaction of sulfated Y1680 in FVIII-a3 and VWF-R816, which, when mutated, leads to severe hemophilia A or VWD type 2N, respectively. These results provide insight on this key coagulation complex, explain the structural basis of many hemophilia A and VWD type 2N mutations, and inform studies to further elucidate how VWF dissociates rapidly from FVIII upon activation.

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Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor.

Cited by 258 publications

References 40 publications

Studies on factor VIII toward a new therapeutic for hemophilia A

Studies on factor VIII toward a new therapeutic for hemophilia A

Vitamin K-Dependent Proteins in Skeletal Development and Disease

Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy

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