Abstract:
:Human ADAMTS13 is a multidomain protein with metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains, followed by 7 additional T domains and 2 CUB (complement components C1r and C1s, sea urchin protein Uegf, and bone morphogenetic protein-1) domains. ADAMTS13 inhibits the growth of von Willebrand factor (VWF)-platelet aggregates by cleaving the cryptic Tyr1605-Met1606 bond in the VWF A2 domain. ADAMTS13 is regulated by substrate-induced allosteric activation; without shear stress, the distal T8-CUB domains markedly inhibit VWF cleavage, and binding of VWF domain D4 or selected monoclonal antibodies (MAbs) to distal ADAMTS13 domains relieves this autoinhibition. By small angle X-ray scattering (SAXS), ADAMTS13 adopts a hairpin-like conformation with distal T7-CUB domains close to the proximal MDTCS domains and a hinge point between T4 and T5. The hairpin projects like a handle away from the core MDTCS and T7-CUB complex and contains distal T domains that are dispensable for allosteric regulation. Truncated constructs that lack the T8-CUB domains are not autoinhibited and cannot be activated by VWF D4 but retain the hairpin fold. Allosteric activation by VWF D4 requires T7, T8, and the 58-amino acid residue linker between T8 and CUB1. Deletion of T3 to T6 produced the smallest construct (delT3-6) examined that could be activated by MAbs and VWF D4. Columba livia (pigeon) ADAMTS13 (pADAMTS13) resembles human delT3-6, retains normal activation by VWF D4, and has a SAXS envelope consistent with amputation of the hairpin containing the dispensable T domains of human ADAMTS13. Our findings suggest that human delT3-6 and pADAMTS13 approach a "minimal" structure for allosterically regulated ADAMTS13.
journal_name
Bloodjournal_title
Bloodauthors
Zhu J,Muia J,Gupta G,Westfield LA,Vanhoorelbeke K,Tolia NH,Sadler JEdoi
10.1182/blood-2018-11-886309subject
Has Abstractpub_date
2019-04-25 00:00:00pages
1909-1918issue
17eissn
0006-4971issn
1528-0020pii
blood-2018-11-886309journal_volume
133pub_type
杂志文章相关文献
BLOOD文献大全abstract::Platelet factor 4 (PF4) serves as a lineage-specific marker of megakaryocyte development. We previously identified two positively acting sequences in the human platelet factor 4 (hPF4) gene promoter that synergized to drive high-level luciferase reporter gene expression in vitro. Using portions of the hPF4 5'-flanking...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1998-04-01 00:00:00
abstract::Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1993-12-15 00:00:00
abstract::Infection by human immunodeficiency virus type 1 (HIV-1) results in a progressive depletion of CD4+ T lymphocytes, leading to fatal immunodeficiency. The mechanisms causing the marked loss of CD4+ T lymphocytes are incompletely understood. However, several lines of evidence indicate that direct cytopathology mediated ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-08-01 00:00:00
abstract::Factor VII levels have been studied in hemophilia A and B plasmas and normal controls in a controlled, prospective study. Three assay methods were used: a standard clotting assay (FVIIc-A); a modified clotting assay (FVIIc-B) (Seligsohn et al, Blood 52:978-988, 1978); and a coupled amidolytic assay. By the FVIIc-B ass...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1985-04-01 00:00:00
abstract::Hematopoietic function of some aplastic anemia (AA) patients is dependent on the administration of cyclosporine (CyA). To investigate whether certain HLA class II genes are associated with susceptibility to such CyA-dependent AA, we determined the HLA class II alleles of 59 AA patients treated with CyA. Among 26 patie...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-12-15 00:00:00
abstract::Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) i...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2009-01-198697
更新日期:2009-07-09 00:00:00
abstract::Donor-matched transplantation of hematopoietic stem cells (HSCs) is widely used to treat hematologic malignancies but is associated with high mortality. The expansion of HSC numbers and their mobilization into the bloodstream could significantly improve therapy. We report here that adult mice conditionally deficient f...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-04-280305
更新日期:2010-12-09 00:00:00
abstract::The mouse Pim-1 gene encodes two cytoplasmic serine-threonine-specific protein kinases. The gene has been found to be activated (overexpressed) by retroviral insertion in hematopoietic tumors in mice. Transgenic mice that overexpress Pim-1 (E mu-Pim-1) have a low incidence of spontaneous T-cell lymphomas and an increa...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1993-09-01 00:00:00
abstract::There has been increasing interest in the involvement of mammalian homeobox (HOX) genes in hematopoietic regulation. The HOX genes are clustered in 4 chromosomes in mice and humans. In general, 5' end HOX gene expression is predominant in hematopoietic stem cell populations, whereas 3' end HOX gene expression are prim...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-04-15 00:00:00
abstract::HIV/AIDS has long been at the forefront of the development of gene- and cell-based therapies. Although conventional gene therapy approaches typically involve the addition of anti-HIV genes to cells using semirandomly integrating viral vectors, newer genome editing technologies based on engineered nucleases are now all...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2016-01-678144
更新日期:2016-05-26 00:00:00
abstract::The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1993-06-15 00:00:00
abstract::Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-01-330738
更新日期:2011-10-20 00:00:00
abstract::Interphase cytogenetics by means of in situ hybridization with the chromosome 12-specific biotinylated alpha satellite DNA probe pSP 12-1 was used for the study of trisomy 12, the most common chromosomal abnormality in chronic lymphocytic leukemia. In situ hybridization was performed on methanol/acetic acid fixed cell...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-08-01 00:00:00
abstract::JAK3 is a tyrosine kinase that associates with the common γ chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants tran...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2014-04-566687
更新日期:2014-11-13 00:00:00
abstract::The timely clearance of apoptotic neutrophils from inflammation sites is an important function of macrophages; however, the role of macrophages in maintaining neutrophil homeostasis under steady-state conditions is less well understood. By conditionally deleting the antiapoptotic gene cellular FLICE-like inhibitory pr...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-01-265959
更新日期:2011-01-13 00:00:00
abstract::The role of platelets in hemostasis and thrombosis is clearly established; however, the mechanisms by which platelets mediate inflammatory and immune pathways are less well understood. Platelets interact and modulate the function of blood and vascular cells by releasing bioactive molecules. Although the platelet is an...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-12-396440
更新日期:2012-06-28 00:00:00
abstract::To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.2018882555
更新日期:2019-07-11 00:00:00
abstract::To test the hypothesis that skeletal muscle myosins can directly influence blood coagulation and thrombosis, ex vivo studies of the effects of myosin on thrombogenesis in fresh human blood were conducted. Addition of myosin to blood augmented the thrombotic responses of human blood flowing over collagen-coated surface...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-03-707679
更新日期:2016-10-06 00:00:00
abstract::Despite potential clinical importance, target cells for mother-to-child transmission of HIV-1 have not yet been identified. Cord blood-derived CD4(+) T cells are largely naive and do not express CCR5, the mandatory coreceptor for transmitted HIV-1 R5 strains in infants. In the present study, we demonstrate that in the...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-06-437566
更新日期:2012-11-22 00:00:00
abstract::Relapse following remission induction chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). To investigate the mechanism of relapse, 27 matched diagnosis and relapse ALL samples were analyzed for clonal populations using polymerase chain reaction...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-01-067785
更新日期:2007-07-15 00:00:00
abstract::The synthetic cytokine (Synthokine) SC-55494 is a high-affinity interleukin-3 (IL-3) receptor ligand that stimulates greater in vitro multilineage hematopoietic activity than native IL-3, while inducing no significant increase in inflammatory activity relative to native IL-3. The aim of this study was to investigate t...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-01-15 00:00:00
abstract::The composition of the erythrocyte plasma membrane is extensively modified during the intracellular growth of the malaria parasite Plasmodium falciparum. It has been previously shown that an 80-kD phosphoprotein is associated with the plasma membrane of human red blood cells (RBCs) infected with trophozoite/schizont s...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-06-01 00:00:00
abstract::Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients w...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2018-06-846816
更新日期:2018-09-27 00:00:00
abstract::Human cyclin A1 is a newly cloned, tissue-specific cyclin that is prominently expressed in normal testis. In this study, we showed that cyclin A1 was highly expressed in a subset of leukemia samples from patients. The highest frequency of cyclin A1 overexpression was observed in acute myelocytic leukemias, especially ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-03-15 00:00:00
abstract::We previously reported that sphingosine 1-phosphate (S1P) regulates peritoneal B-cell trafficking and subsequent intestinal IgA production, but the underlying mechanisms remain obscure. We demonstrate here that nuclear factor kappaB-inducing kinase (NIK) is involved in the regulation of S1P-mediated trafficking of per...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-10-120071
更新日期:2008-05-01 00:00:00
abstract::The expression of Lewis fucosyltransferase (FT) mRNA was examined in gastric mucosa from two Lewis-positive [Le(+)] and two Lewis-negative [Le(-)] individuals. Northern blot analysis demonstrated that levels of mRNA were similar in both Le(+) and Le(-) gastric mucosa. We isolated the protein-coding region of the Lewis...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1993-11-01 00:00:00
abstract::The endothelial cell protein C/activated protein C receptor (EPCR) is located primarily on the surface of the large vessels of the vasculature. In vitro studies suggest that it is involved in the protein C anticoagulant pathway. We report the organization and nucleotide sequence of the human EPCR gene. It spans approx...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1999-07-15 00:00:00
abstract::Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2013-09-528018
更新日期:2014-03-20 00:00:00
abstract::Fcgamma receptors (FcgammaRs) on mononuclear phagocytes trigger autoantibody and immune complex-induced diseases through coupling the self-reactive immunoglobulin G (IgG) response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcRgamma-based activation is critical in the ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2008-05-158477
更新日期:2009-01-29 00:00:00
abstract::Previous studies suggested a role for prostaglandins or thromboxane A2, or both in the exposure of fibrinogen receptors on normal platelets in response to several aggregating agents. Platelets from diabetics are known to be more sensitive to aggregating agents and to produce more prostaglandins and thromboxane than pl...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00