Residues Phe342–Asn346 of Activated Coagulation Factor IX Contribute to the Interaction with Low Density Lipoprotein Receptor-related Protein

Rohlena, Jakub; Kolkman, Joost A.; Boertjes, Ria; Mertens, Koen; Lenting, Peter J.

doi:10.1074/jbc.m209097200

Cited by 25 publications

(19 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5) and by Vreys et al (Vreys and David, 2007;Vreys et al, 2005) add heparanase to the growing list of enzymes that bind LRP, and further support a critical role for the LRP system in the uptake and clearance of proteases and glucuronidases from the extracellular environment. Furthermore, the calculated affinity of heparanase for LRP (Kd = 2-3.5 nM) is in the range, or even higher than that found for most other LRP ligands (Croucher et al, 2006;Hahn-Dantona et al, 2001;Muramatsu et al, 2000;Page et al, 2006;Rohlena et al, 2003), supporting its biological relevance.…”

Section: Discussionmentioning

confidence: 75%

Low and high affinity receptors mediate cellular uptake of heparanase

Ben-Zaken

Shafat

Gingis-Velitski

et al. 2008

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Heparanase is an endoglycosidase which cleaves heparan sulfate and hence participates in degradation and remodeling of the extracellular matrix. Importantly, heparanase activity correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix barrier. Heparanase has been characterized as a glycoprotein, yet glycan biochemical analysis was not performed to date. Here, we applied the Qproteome ™ GlycoArray kit to perform glycan analysis of heparanase, and compared the kit results with the more commonly used biochemical analyses. We employed fibroblasts isolated from patients with I-cell disease (mucolipidosis II), fibroblasts deficient of low density lipoprotein receptor-related protein and fibroblasts lacking mannose 6-phosphate receptor, to explore the role of mannose 6-phosphate in heparanase uptake. Iodinated heparanase has been utilized to calculate binding affinity. We provide evidence for hierarchy of binding to cellular receptors as a function of heparanase concentration. We report the existence of a high affinity, low abundant (i.e., low density lipoprotein receptor-related protein, mannose 6-phosphate receptor), as well as a low affinity, high abundant (i.e., heparan sulfate proteoglycan) receptors that mediate heparanase binding, and suggest that these receptors cooperate to establish high affinity binding sites for heparanase, thus maintaining extracellular retention of the enzyme tightly regulated.

show abstract

Section: Discussionmentioning

confidence: 75%

Low and high affinity receptors mediate cellular uptake of heparanase

Ben-Zaken

Shafat

Gingis-Velitski

et al. 2008

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

show abstract

“…This overlap might be a coincidence, as these regions are well‐exposed at the molecular surface of FVIII and therefore fulfill criteria for interactive sites and inhibitor epitopes. Alternatively, recombinant LRP1 fragments are potent inhibitors of FVIIIa–FIXa‐mediated FXa generation [26], pointing to a potential regulatory role of LRP1 in the down‐regulation of the tenase complex.…”

Section: Location Of Lrp1 Interactive Sites In Fviiimentioning

confidence: 99%

Clearance mechanisms of von Willebrand factor and factor VIII

Lenting

Schooten

Denis

2007

Journal of Thrombosis and Haemostasis

135

126

View full text Add to dashboard Cite

“…29 Second, fine mapping within the protease domain was performed using purified hFIX chimeras with FX replacements in surface loops 223 to 227, 258 to 267, or 315 to 323. 30 Together these loops comprise the human/rhesus differences in positions 226, 227, 261, 315 and 321. 31 Mapping was performed in a standard ELISA format in which wells were coated with appropriate anti-FIX or anti-FX antibodies (0.1 g/well).…”

Section: Epitope Mapping Of Anti-human Fix Antibodiesmentioning

confidence: 99%

Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver

Nathwani

Gray

et al. 2006

Blood

Self Cite

371

381

View full text Add to dashboard Cite

Transduction with recombinant adenoassociated virus (AAV) vectors is limited by the need to convert its single-stranded (ss) genome to transcriptionally active double-stranded (ds) forms. For AAVmediated hemophilia B (HB) gene therapy, we have overcome this obstacle by constructing a liver-restricted mini-human factor IX (hFIX) expression cassette that can be packaged as complementary dimers within individual AAV particles. Molecular analysis of murine liver transduced with these self-complementary (sc) vectors demonstrated rapid formation of active ds-linear genomes that persisted stably as concatamers or monomeric circles. This unique property resulted in a 20-fold improvement in hFIX expression in mice over comparable ssAAV vectors. Administration of only 1 ؋ 10 10 scAAV particles led to expression of hFIX at supraphysiologic levels (8I U/mL) and correction of the bleeding diathesis in FIX knock-out mice. Of importance, therapeutic levels of hFIX (3%-30% of normal) were achieved in nonhuman primates using a significantly lower dose of scAAV than required with ssAAV. Furthermore, AAV5-pseudotyped scAAV vectors mediated successful transduction in macaques with pre-existing immunity to AAV8. Hence, this novel vector represents an important advance for hemophilia B gene therapy. IntroductionThe liver is an important target for gene therapy of a variety of genetic disorders, one of which is hemophilia B (HB), a lifethreatening bleeding disorder that arises from mutations in the blood coagulation factor IX (FIX) gene. By maintaining plasma FIX levels above 1% of normal (Ͼ 0.05 g/mL), the incidence of spontaneous hemorrhage is dramatically reduced and so the therapeutic end point for HB gene therapy is modest. 1 Currently, adeno-associated virus (AAV) vectors are the most promising for HB gene therapy and have been the focus of 2 recent clinical trials. 2 Efficient transduction with AAV is, however, limited by the need to convert its single-stranded (ss) genome into transcriptionally active double-stranded (ds) forms in target cells because of its dependence on host-cell-mediated DNA synthesis of the leading strand 3 or annealing of complementary genomes derived from separate virions. 4 Coinfection with adenovirus 5 or priming the target tissues with genotoxic agents 6,7 can enhance ds transgene formation, but the clinical use of these approaches is limited by potential toxicity. Rapid uncoating of the viral genome, as recently described with AAV8 vectors, allows efficient annealing of the ssAAV provirus to form double-stranded genomes. This unique biologic property is responsible for the 10-to 100-fold higher transduction of the liver with rAAV8 when compared with AAV2 vectors in murine models. [8][9][10] Even so, almost 10 13 AAV8 vector particles are required to achieve 100% hepatocyte transduction in mice, a level that is required for successful gene therapy of some metabolic disorders of the liver. 11 This high vector dose is problematic because it may (1) Supported by The Assisi Foundation of Memphis; the Ame...

show abstract

Residues Phe342–Asn346 of Activated Coagulation Factor IX Contribute to the Interaction with Low Density Lipoprotein Receptor-related Protein

Cited by 25 publications

References 58 publications

Low and high affinity receptors mediate cellular uptake of heparanase

Low and high affinity receptors mediate cellular uptake of heparanase

Clearance mechanisms of von Willebrand factor and factor VIII

Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver

Contact Info

Product

Resources

About