Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment.
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http://dx.doi.org/10.1038/s41586-022-04952-2 | DOI Listing |
Development
January 2025
Institute of Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.
In the mammalian ureters, the lamina propria presents as a prominent layer of connective tissue underneath the urothelium. Despite its important structural and signaling functions, little is known how the lamina propria develops. Here, we show that in the murine ureter, the lamina propria arises at late fetal stages and massively increases by fibrocyte proliferation and collagen deposition after birth.
View Article and Find Full Text PDFJ Vet Med Sci
January 2025
Department of Small Animal Internal Medicine II, School of Veterinary Medicine, Kitasato University.
This study investigated the anti-inflammatory effects of water-dispersible hesperetin (WD-Hpt) in an endotoxin-induced uveitis (EIU) rat model. The rats were orally administered 10, 25, or 50 mg/kg WD-Hpt immediately after lipopolysaccharide (LPS) injection at the concentration of 200 μg. Clinical scores, cellular inflammation, the aqueous humor (ApH) protein concentration, as well as the levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) in AqH, and histopathological grades were assessed.
View Article and Find Full Text PDFInt J Biol Macromol
January 2025
Nanjing University of Chinese Medicine/National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing 210029, China; Jiangsu Province Key Laboratory of High Technology Research, Nanjing 210029, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, China. Electronic address:
In recent years, polysaccharides derived from natural sources have garnered significant attention due to their safety and potential anti-osteoporotic effects. This review provides a comprehensive overview of the sources, distribution, structures, and mechanisms of anti-osteoporosis polysaccharides, as well as an investigation into their structure-activity relationships. Over thirty distinct, homogenous polysaccharides with anti-osteoporosis properties have been extracted from natural sources, primarily categorized as glucans, fructans, galactomannans, glucomannans, and various other heteropolysaccharides.
View Article and Find Full Text PDFDev Biol
January 2025
University of Aberdeen, School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK. Electronic address:
Signals from the lens regulate multiple aspects of eye development, including establishment of eye size, patterning of the presumptive iris and ciliary body in the anterior optic cup and migration and differentiation of neural crest cells. To advance understanding of the molecular mechanism by which the lens regulates eye development, we performed transcriptome profiling of embryonic chicken retinas after lens removal. Genes associated with nervous system development were upregulated in lens-removed eyes, but the presumptive ciliary body and iris region did not adopt a neural retina identity following lens removal.
View Article and Find Full Text PDFArch Oral Biol
January 2025
Pharmaceutical Sciences and Technology Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; Center of Excellent in Natural Products and Nanoparticles (NP2), Chulalongkorn University, Bangkok, Thailand.
Objective: Asiaticoside has the capacity to induce osteogenic differentiation of human periodontal ligament cells (hPDLCs) through Wnt (Wingless-related integration site) signaling. A modified chemical structure (by removing glycoside side chain), referred to as asiatic acid methyl ester (AA1), has been constructed and evaluated for its capacity to induce osteogenic differentiation.
Design: hPDLCs viability was determined by MTT assay.
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