Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation.
The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin. This shows minimal overlap with the heparin binding site and highlights a key role for this region of sclerostin in protein interactions associated with the inhibition of Wnt signaling. The conserved N- and C-terminal arms of sclerostin were found to be unstructured, highly flexible, and unaffected by heparin binding, which suggests a role in stabilizing interactions with target proteins.
Veverka
Vaclav
V
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
Henry
Alistair J
AJ
Slocombe
Patrick M
PM
Ventom
Andrew
A
Mulloy
Barbara
B
Muskett
Frederick W
FW
Muzylak
Mariusz
M
Greenslade
Kevin
K
Moore
Adrian
A
Zhang
Li
L
Gong
Jianhua
J
Qian
Xueming
X
Paszty
Chris
C
Taylor
Richard J
RJ
Robinson
Martyn K
MK
Carr
Mark D
MD
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005819:Genetic Markers / Q000235:genetics; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010012:Osteogenesis / Q000502:physiology*; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D006493:Heparin