Stereoselective fatty acylation is essential for the release of lipidated WNT proteins from the acyltransferase Porcupine (PORCN)
| Autor: | Lawrence G. Lum, Jeremiah Herbert, Yuyong Ma, Chuo Chen, Chengwei Zhang, James Kim, Nageswari Yarravarapu, Rubina Tuladhar |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell signaling Acylation Xenopus Lipid-anchored protein Biochemistry Mice 03 medical and health sciences Chlorocebus aethiops Animals Humans Caenorhabditis elegans Wnt Signaling Pathway Molecular Biology Mice Knockout chemistry.chemical_classification 030102 biochemistry & molecular biology Chemistry Fatty Acids Wnt signaling pathway Membrane Proteins Fatty acid Schistosoma mansoni Cell Biology Cell biology PORCN HEK293 Cells 030104 developmental biology Acyltransferase COS Cells lipids (amino acids peptides and proteins) Fatty acylation Chickens Protein Processing Post-Translational Acyltransferases HeLa Cells Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 294:6273-6282 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.007268 |
| Popis: | The maintenance of adult animal tissues depends upon highly conserved intercellular signaling molecules that include the secreted WNT proteins. Although it is generally accepted that lipidation of WNTs by the acyltransferase Porcupine (PORCN) and their subsequent recognition by the Wntless (WLS) protein is essential for their cellular secretion, the molecular understanding of this process remains limited. Using structurally diverse fatty acyl donor analogs and mouse embryonic fibroblasts expressing PORCN protein from different metazoan phyla, we demonstrate here that PORCN active-site features, which are conserved across the animal kingdom, enforce cis-Δ9 fatty acylation of WNTs. Aberrant acylation of a WNT with an exogenously supplied trans-Δ9 fatty acid induced the accumulation of WNT-PORCN complexes, suggesting that the fatty acyl species is critical for the extrication of lipidated WNTs from PORCN. Our findings reveal a previously unrecognized fatty acyl–selective checkpoint in the manufacturing of a lipoprotein that forms a basis for WNT signaling sensitivity to trans fats and to PORCN inhibitors in clinical development. |
| Databáze: | OpenAIRE |
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