Domain-specific modification of heparan sulfate by Qsulf1 modulates the binding of the bone morphogenetic protein antagonist Noggin.
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.
Viviano
Beth L
BL
Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Paine-Saunders
Stephenie
S
Gasiunas
Nijole
N
Gallagher
John
J
Saunders
Scott
S
D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004187:Disaccharides / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006497:Heparan Sulfate / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D009005:Monosaccharides / Q000737:chemistry; D009608:Nitrous Acid / Q000494:pharmacology; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D013429:Sulfatases / Q000737:chemistry*; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004187:Disaccharides; D006493:Heparin; D006497:Heparan Sulfate; D009005:Monosaccharides; D009608:Nitrous Acid; D011506:Proteins; D011518:Proto-Oncogene Proteins; D013429:Sulfatases; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000099176:Noggin Protein; C525813:bmp4 protein, zebrafish; C477242:QSulf1