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STRUCTURE OF THE WNT DEACYLASE NOTUM FROM DROSOPHILA - CRYSTAL FORM I - 2.4A
Structural highlights
FunctionNOTUM_DROME Carboxylesterase that acts as a key negative regulator of the Wnt signaling pathway by specifically mediating depalmitoleoylation of WNT proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors (PubMed:25731175). Also acts as a regulator of long-range activity of Hedgehog (hh), possibly by regulating the switch between low and high level hh pathway signaling (PubMed:20412775, PubMed:22872085).[UniProtKB:Q6P988][1] [2] [3] Publication Abstract from PubMedSignalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase. Notum deacylates Wnt proteins to suppress signalling activity.,Kakugawa S, Langton PF, Zebisch M, Howell SA, Chang TH, Liu Y, Feizi T, Bineva G, O'Reilly N, Snijders AP, Jones EY, Vincent JP Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25. PMID:25731175[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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