2k8p
From Proteopedia
Characterisation of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation
Structural highlights
Disease[SOST_HUMAN] Defects in SOST are the cause of sclerosteosis type 1 (SOST1) [MIM:269500]. An autosomal recessive sclerosing bone dysplasia characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients.[1] [2] [3] Defects in SOST are a cause of van Buchem disease (VBCH) [MIM:239100]. An autosomal recessive sclerosing bone dysplasia characterized by endosteal hyperostosis of the mandible, skull, ribs, clavicles, and diaphyses of the long bones. Affected patients present a symmetrically increased thickness of bones, most frequently found as an enlarged jawbone, but also an enlargement of the skull, ribs, diaphysis of long bones, as well as tubular bones of hands and feet. The clinical consequence of increased thickness of the skull include facial nerve palsy causing hearing loss, visual problems, neurological pain, and, very rarely, blindness as a consequence of optic atrophy. Serum alkaline phosphatase levels are elevated. Note=A 52 kb deletion downstream of SOST results in SOST transcription suppression causing van Buchem disease.[4] Defects in SOST are a cause of craniodiaphyseal dysplasia autosomal dominant (CDD) [MIM:122860]. A severe bone dysplasia characterized by massive generalized hyperostosis and sclerosis, especially involving the skull and facial bones. The sclerosis is so severe that the resulting facial distortion is referred to as 'leontiasis ossea' (leonine faces) and the bone deposition results in progressive stenosis of craniofacial foramina. Respiratory obstruction due to choanal stenosis compromises the clinical outcomes of affected patients. Note=Heterozygous mutations located in the secretion signal of the SOST gene prevent sclerostin secretion and can be responsible for craniodiaphyseal dysplasia.[5] Function[SOST_HUMAN] Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.[6] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation.,Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, Muzylak M, Greenslade K, Moore A, Zhang L, Gong J, Qian X, Paszty C, Taylor RJ, Robinson MK, Carr MD J Biol Chem. 2009 Apr 17;284(16):10890-900. Epub 2009 Feb 10. PMID:19208630[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
Categories: Human | Large Structures | Carr, M D | Gong, J | Greenslade, K | Henry, A J | Moore, A | Mulloy, B | Muskett, F W | Muzylak, M | Paszty, C | Qian, X | Robinson, M K | Slocombe, P M | Taylor, R J | Ventom, A | Veverka, V | Zhang, L | Alternative splicing | Bone formation | Glycoprotein | Secreted | Signaling protein | Wnt signalling pathway
