TY  - JOUR
A1  - Mueller, Thomas D.
A1  - Fiebig, Juliane E.
A1  - Weidauer, Stella E.
A1  - Qiu, Li-Yan
A1  - Bauer, Markus
A1  - Schmieder, Peter
A1  - Beerbaum, Monika
A1  - Zhang, Jin-Li
A1  - Oschkinat, Hartmut
A1  - Sebald, Walter
T1  - The Clip-Segment of the von Willebrand Domain 1 of the BMP Modulator Protein Crossveinless 2 Is Preformed
JF  - Molecules
N2  - Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand-specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop.
KW  - bone morphogenetic proteins
KW  - TGF-β superfamily
KW  - BMP antagonist
KW  - protein-protein recognition
KW  - NMR spectroscopy
KW  - von Willebrand type C domain
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97196
ER  - 
TY  - JOUR
A1  - van Dinther, Maarten
A1  - Zhang, Juan
A1  - Weidauer, Stella E.
A1  - Boschert, Verena
A1  - Muth, Eva-Maria
A1  - Knappik, Achim
A1  - de Gorter, David J. J.
A1  - van Kasteren, Puck B.
A1  - Frisch, Christian
A1  - Müller, Thomas D.
A1  - ten Dijke, Peter
T1  - Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling
JF  - PLoS ONE
N2  - Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with \([^{125} I]\) Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin. Finally, an anti-Sclerostin antibody inhibited the internalization of Sclerostin-GFP and binding of Sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of Sclerostin on canonical Wnt-induced responses.
KW  - gene
KW  - rat model
KW  - Dickkopf proteins
KW  - postmenopausal osteoporosis
KW  - increases bone-formation
KW  - WNT
KW  - LRP6
KW  - density
KW  - receptor
KW  - ligand
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130981
VL  - 8
IS  - 4
ER  -