Notum deacylates Wnts to suppress signalling activity
By Satoshi Kakugawa, Paul F. Langton, M. Zebisch, Steven A. Howell, Tao-Hsin Chang, Yan Liu, T. Feizi, Ganka Bineva, N. O'Reilly, A. Snijders and 2 more. 2015
297 citations recorded by the source corpus.
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.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
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Citations in the corpus
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, background): “Carboxylesterase Notum is a serine hydrolase enzyme that catalyses the delipidation of Wnt proteins and so regulates Wnt signalling [1,2].”
- Stereoselective fatty acylation is essential for the release of lipidated WNT proteins from the acyltransferase Porcupine (PORCN) (2019, background): “At the same time, the WNT deacylase NOTUM incorporates several residues within its active site as part of a steric gate that precludes the binding of FAs without a cis- 9 double bond (30).”
- Structural basis of WLS/Evi-mediated Wnt transport and secretion (2020, background): “More recently, the structures of Notum, a Wnt deacylase, and Dally-like protein (Dlp), a GPI-anchored glypican that facilitates Wnt diffusion on cell surfaces, also demonstrated binding of PAM to domains in the extracellular space (Kakugawa et al., 2015; McGough et al., 2020).”
- Single-Cell Profiling and SCOPE-Seq Reveal Lineage Dynamics of Adult Ventricular-Subventricular Zone Neurogenesis and NOTUM as a Key Regulator (2020, unknown): “, 2015), it but can also be retained at the cell surface via binding to glycosaminoglycans on glypicans (Kakugawa et al., 2015).”
- Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities (2022, background): “Both Tiki and Notum act as enzymes to inactivate Wnt proteins.(27,28) Ub LRP RNF43/ZNF3”
- Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, unknown): “Loss of function mutations of PORCN and WLS that block the acylation and delivery of Wnts cause early embryonic lethality in mouse knockout models (Barrott et al., 2011; Biechele et al., 2011; Fu et al., 2009).”
- In vitro reconstitution of Wnt acylation reveals structural determinants of substrate recognition by the acyltransferase human Porcupine (2018, background): “Existing structures reveal that proteins that are involved in the biosynthesis of palmitoleoyl-CoA (i.e. stearoyl-CoA desaturase (SCD)) (34, 35) or proteins that specifically recognize the unsaturated aliphatic chain (i.e. Wnt deacylase Notum) (36) assert selectivity for the unsaturated fatty acyl g”