Autoregulation of von Willebrand factor function by a disulfide bond switch

Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this “mechanopresentation” remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ~75% of VWF subunits in healthy human donor plasma but in just ~25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.: This study was supported by grants from the National Health and Medical Research Council of Australia (P.J.H.), Royal College of Pathologists Foundation Kanematsu/Novo Nordisk Research Award (F.P. and L.J.), Diabetes Australia Research Trust grant G179720 and Sydney Medical School Early-Career Researcher Kickstart Grant (L.J.), National Heart Foundation of Australia Postdoctoral Fellowship (101285) (L.J.) and British Heart Foundation Intermediate Basic Science Research Fellowship (FS/11/51/28920) (B.M.L.), Deutsche Forschungsgemeinschaft (research unit FOR 1543 to C.A.-S., C.B., and F.G.), the Center for Modelling and Simulation in the Biosciences postdoctoral program of the Heidelberg University (A.B.), and the Klaus Tschira Foundation (F.G.). B.L. was supported by the Dutch Thrombosis Foundation through grant number 2016-03.

In vivo modulation of angiogenesis by beta 2 glycoprotein I

Beta 2 glycoprotein I (β2GPI) is the major auto antigen in the antiphospholipid syndrome but also interacts with fibrinolytic and angiogenic proteins. The aim of this study was to examine the angiogenic potential of β2GPI in vivo in β2GPI deficient mi

Angiogenic molecules in Hodgkin's disease: Results from sequential serum analysis

Increased angiogenic activity has been demonstrated in lymphoproliferative diseases including Hodgkin's disease. In the current study, the levels of circulating angiogenic molecules in 60 Hodgkin's patients were determined prior to and after treatment and correlated to disease stage and prognostic score. Hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were increased in Hodgkin's patients in comparison to healthy controls (p<0.001). Angiogenin and angiopoietin-2 levels did not differ from controls. HGF, VEGF, TNF-α and angiogenin decreased significantly in Hodgkin's patients after standard treatment (p<0.001 for HGF, p<0.05 for VEGF, TNF-α and angiogenin). Furthermore, HGF and TNF-α increased with advancing stage of disease (p<0.05). HGF and VEGF correlated significantly with IL-6 (r=0.56, p<0.0005 and r=0.57, p<0.001 respectively). In conclusion, Hodgkin's disease displays an angiogenic activity as depicted by the increased serum levels of a number of angiogenic cytokines. HGF seems to be the prominent molecule in Hodgkin's disease, which may be used to monitor the disease status and the response to treatment. Copyright © by Biolife, s.a.s

Thymoma with immunodeficiency (Good's syndrome): Review of the literature apropos three cases

Good's syndrome is the association of thymoma with immunodeficiency, characterized by hypogammaglobulinaemia, depleted B-cells, diminished T-cells and inversion of the CD4/CD8 ratio. The initial clinical presentation is either with a mass lesion-thymoma that is usually benign, or with recurrent infections due to immunodeficiency. Thymectomy usually favourably affects associated conditions, such as pure red cell aplasia, but does not improve hypogammaglobulinaemia, thus the patient remains dependent on intravenous immune globulin and prone to infections. Infections usually affect the respiratory and/or the gastrointestinal tract. Common respiratory, opportunistic, and eventually life-threatening infections may occur. Moreover, patients with Good's syndrome may present other haematological conditions. We report 3 cases with long follow-up, sharing some common manifestations of the syndrome, but also showing unique features. The principal features of this rare syndrome are further discussed. © 2006 Taylor & Francis

Angiogenesis-related growth factors and cytokines in the serum of patients with B non-Hodgkin lymphoma; relation to clinical features and response to treatment

Increased angiogenesis has been shown to be a feature of non-Hodgkin lymphomas (NHL). In the current study, the pretreatment levels of circulating molecules related to angiogenesis were determined in 49 B-cell NHL patients and correlated with histological grade, disease stage and prognostic score. In 25 patients, the same molecules were defined after standard treatment. Vascular endothelial growth factor (VEGF), angiogenin, interleukin-2 (IL-2), IL-6, IL-8 and IL-16 were measured. Increased levels of VEGF, IL-6 and IL-8 were found in the whole group of untreated patients in comparison with normal controls (P < 0.05), whereas, IL-2 was higher in the subgroup of indolent NHL. Overall, there was no significant decrease in the levels of these molecules after treatment. However, by stratification into group of responders vs. non-responders pretreatment IL-8 was significantly increased whereas IL-16 was decreased in the subgroup of complete responders. According to the REAL classification IL-2 was higher in the low risk compared with intermediate plus high-risk group. There was no association with disease stage or the International Prognostic Score. Both indolent and aggressive B cell lymphomas have increased production of angiogenic mediators and cytokines with IL-8 and IL-16 potentially reflecting the response to treatment. © 2007 The Authors