4uzk

STRUCTURE OF THE WNT DEACYLASE NOTUM FROM DROSOPHILA - CRYSTAL FORM II - 1.9ASTRUCTURE OF THE WNT DEACYLASE NOTUM FROM DROSOPHILA - CRYSTAL FORM II - 1.9A

Structural highlights

4uzk is a 2 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NOTUM_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 PubMed

Signalling 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

↑ Ayers KL, Gallet A, Staccini-Lavenant L, Thérond PP. The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum. Dev Cell. 2010 Apr 20;18(4):605-20. PMID:20412775 doi:10.1016/j.devcel.2010.02.015
↑ Ayers KL, Mteirek R, Cervantes A, Lavenant-Staccini L, Thérond PP, Gallet A. Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling. Development. 2012 Sep;139(17):3168-79. PMID:22872085 doi:10.1242/dev.078402
↑ 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. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25. PMID:25731175 doi:http://dx.doi.org/10.1038/nature14259
↑ 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. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25. PMID:25731175 doi:http://dx.doi.org/10.1038/nature14259

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OCA

[1] Ayers KL, Gallet A, Staccini-Lavenant L, Thérond PP. The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum. Dev Cell. 2010 Apr 20;18(4):605-20. PMID:20412775 doi:10.1016/j.devcel.2010.02.015

[2] Ayers KL, Mteirek R, Cervantes A, Lavenant-Staccini L, Thérond PP, Gallet A. Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling. Development. 2012 Sep;139(17):3168-79. PMID:22872085 doi:10.1242/dev.078402

[3] 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. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25. PMID:25731175 doi:http://dx.doi.org/10.1038/nature14259

[4] 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. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25. PMID:25731175 doi:http://dx.doi.org/10.1038/nature14259

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