Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.

2.50
Hdl Handle:
http://hdl.handle.net/10541/78451
Title:
Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.
Authors:
Viviano, Beth L; Paine-Saunders, Stephenie; Gasiunas, Nijole; Gallagher, John T; Saunders, Scott
Abstract:
We have reported previously that Noggin is a heparin-binding protein and associates with the cell surface through heparan sulfate proteoglycans, where it remains functional for the binding of bone morphogenetic proteins (BMPs). Here we report that the binding of Noggin to the cell surface is highly selective for heparan sulfate and that specific structural features are required for the interaction. Noggin binds most efficiently to heparin sequences composed of 10 or more monosaccharides; N-, 6-O-, and 2-O-sulfates contribute to this interaction. In addition, we have shown that the developmentally regulated endosulfatase Qsulf1 selectively removes sulfate groups from the 6-O position of sugars within the most highly sulfated S domains of heparan sulfate, whereas 6-O-sulfates in the NA/NS domains are not substrates for the enzyme. The activity of Qsulf1 in cells in culture results in the release of Noggin from the cell surface and a restoration of BMP responsiveness to the cells. This shows that Noggin binds to the S domains of heparan sulfate and provides evidence that, in addition to modulating Wnt signaling in vivo by the release of heparan sulfate bound Wnt, Qsulf1 also modulates BMP signaling by the release of surface-bound Noggin.
Affiliation:
Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Citation:
Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin. 2004, 279 (7):5604-11 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
13-Feb-2004
URI:
http://hdl.handle.net/10541/78451
DOI:
10.1074/jbc.M310691200
PubMed ID:
14645250
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorViviano, Beth L-
dc.contributor.authorPaine-Saunders, Stephenie-
dc.contributor.authorGasiunas, Nijole-
dc.contributor.authorGallagher, John T-
dc.contributor.authorSaunders, Scott-
dc.date.accessioned2009-08-25T11:23:09Z-
dc.date.available2009-08-25T11:23:09Z-
dc.date.issued2004-02-13-
dc.identifier.citationDomain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin. 2004, 279 (7):5604-11 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid14645250-
dc.identifier.doi10.1074/jbc.M310691200-
dc.identifier.urihttp://hdl.handle.net/10541/78451-
dc.description.abstractWe have reported previously that Noggin is a heparin-binding protein and associates with the cell surface through heparan sulfate proteoglycans, where it remains functional for the binding of bone morphogenetic proteins (BMPs). Here we report that the binding of Noggin to the cell surface is highly selective for heparan sulfate and that specific structural features are required for the interaction. Noggin binds most efficiently to heparin sequences composed of 10 or more monosaccharides; N-, 6-O-, and 2-O-sulfates contribute to this interaction. In addition, we have shown that the developmentally regulated endosulfatase Qsulf1 selectively removes sulfate groups from the 6-O position of sugars within the most highly sulfated S domains of heparan sulfate, whereas 6-O-sulfates in the NA/NS domains are not substrates for the enzyme. The activity of Qsulf1 in cells in culture results in the release of Noggin from the cell surface and a restoration of BMP responsiveness to the cells. This shows that Noggin binds to the S domains of heparan sulfate and provides evidence that, in addition to modulating Wnt signaling in vivo by the release of heparan sulfate bound Wnt, Qsulf1 also modulates BMP signaling by the release of surface-bound Noggin.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshBlotting, Western-
dc.subject.meshBone Morphogenetic Protein 4-
dc.subject.meshBone Morphogenetic Proteins-
dc.subject.meshCHO Cells-
dc.subject.meshCarrier Proteins-
dc.subject.meshCell Membrane-
dc.subject.meshCricetinae-
dc.subject.meshDisaccharides-
dc.subject.meshHeparin-
dc.subject.meshHeparitin Sulfate-
dc.subject.meshMicroscopy, Fluorescence-
dc.subject.meshMonosaccharides-
dc.subject.meshNitrous Acid-
dc.subject.meshPrecipitin Tests-
dc.subject.meshProtein Structure, Tertiary-
dc.subject.meshProteins-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshSignal Transduction-
dc.subject.meshSulfatases-
dc.subject.meshTemperature-
dc.subject.meshTime Factors-
dc.subject.meshTransfection-
dc.subject.meshWnt Proteins-
dc.subject.meshZebrafish Proteins-
dc.titleDomain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.en
dc.identifier.journalThe Journal of Biological Chemistryen

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