{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:04:43Z","timestamp":1772168683604,"version":"3.50.1"},"reference-count":89,"publisher":"The Company of Biologists","issue":"24","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100001381","name":"National Research Foundation Singapore","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001381","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"crossref","award":["MOH-000155"],"award-info":[{"award-number":["MOH-000155"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Wnt signaling is essential for normal development and is a therapeutic target in cancer. The enzyme PORCN, or porcupine, is a membrane-bound O-acyltransferase (MBOAT) that is required for the post-translational modification of all Wnts, adding an essential mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2. Inherited mutations in PORCN cause focal dermal hypoplasia, and therapeutic inhibition of PORCN slows the growth of Wnt-dependent cancers. Based on homology to mammalian MBOAT proteins, we developed and validated a structural model of human PORCN. The model accommodates palmitoleoyl-CoA and Wnt hairpin 2 in two tunnels in the conserved catalytic core, shedding light on the catalytic mechanism. The model predicts how previously uncharacterized human variants of uncertain significance can alter PORCN function. Drugs including ETC-159, IWP-L6 and LGK-974 dock in the PORCN catalytic site, providing insights into PORCN pharmacologic inhibition. This structural model enhances our mechanistic understanding of PORCN substrate recognition and catalysis, as well as the inhibition of its enzymatic activity, and can facilitate the development of improved inhibitors and the understanding of disease-relevant PORCN mutants.<\/jats:p>\n                  <jats:p>This article has an associated First Person interview with the joint first authors of the paper.<\/jats:p>","DOI":"10.1242\/jcs.259383","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T05:51:55Z","timestamp":1637733115000},"source":"Crossref","is-referenced-by-count":23,"title":["Structural model of human PORCN illuminates disease-associated variants and drug-binding sites"],"prefix":"10.1242","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7004-9104","authenticated-orcid":false,"given":"Jia","family":"Yu","sequence":"first","affiliation":[{"name":"Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6201-1301","authenticated-orcid":false,"given":"Pei-Ju","family":"Liao","sequence":"additional","affiliation":[{"name":"Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weijun","family":"Xu","sequence":"additional","affiliation":[{"name":"Discovery Chemistry, Experimental Drug Development Centre, 10 Biopolis Road, Chromos, 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie R.","family":"Jones","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8331-992X","authenticated-orcid":false,"given":"David B.","family":"Everman","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8295-0453","authenticated-orcid":false,"given":"Heather","family":"Flanagan-Steet","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7553-6235","authenticated-orcid":false,"given":"Thomas H.","family":"Keller","sequence":"additional","affiliation":[{"name":"Discovery Chemistry, Experimental Drug Development Centre, 10 Biopolis Road, Chromos, 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-850X","authenticated-orcid":false,"given":"David M.","family":"Virshup","sequence":"additional","affiliation":[{"name":"Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore"},{"name":"Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"2022051110290501000_JCS259383C1","doi-asserted-by":"publisher","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: expanding the scope of the protein\u2013ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C2","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"2022051110290501000_JCS259383C3","doi-asserted-by":"publisher","first-page":"W537","DOI":"10.1093\/nar\/gky379","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update","volume":"46","author":"Afgan","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C4","doi-asserted-by":"publisher","first-page":"13507","DOI":"10.1074\/jbc.C117.800136","article-title":"An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase Porcupine","volume":"292","author":"Asciolla","year":"2017","journal-title":"J. Biol. Chem."},{"key":"2022051110290501000_JCS259383C5","doi-asserted-by":"publisher","first-page":"W344","DOI":"10.1093\/nar\/gkw408","article-title":"ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules","volume":"44","author":"Ashkenazy","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C6","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nature14549","article-title":"X-ray structure of a mammalian stearoyl-CoA desaturase","volume":"524","author":"Bai","year":"2015","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C7","doi-asserted-by":"publisher","first-page":"12752","DOI":"10.1073\/pnas.1006437108","article-title":"Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia\/Goltz syndrome","volume":"108","author":"Barrott","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022051110290501000_JCS259383C8","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.devcel.2012.07.011","article-title":"Structural architecture and functional evolution of Wnts","volume":"23","author":"Bazan","year":"2012","journal-title":"Dev. Cell"},{"key":"2022051110290501000_JCS259383C9","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.ydbio.2011.04.029","article-title":"Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos","volume":"355","author":"Biechele","year":"2011","journal-title":"Dev. Biol."},{"key":"2022051110290501000_JCS259383C10","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/nbt.3134","article-title":"Multi-omic data analysis using Galaxy","volume":"33","author":"Boekel","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"2022051110290501000_JCS259383C11","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/ajmg.c.31473","article-title":"Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals","volume":"172","author":"Bostwick","year":"2016","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2022051110290501000_JCS259383C12","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/ejhg.2014.135","article-title":"Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia","volume":"23","author":"Brady","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"2022051110290501000_JCS259383C13","doi-asserted-by":"publisher","first-page":"14166","DOI":"10.1074\/jbc.AC119.009749","article-title":"The ghrelin O-acyltransferase structure reveals a catalytic channel for transmembrane hormone acylation","volume":"294","author":"Campa\u00f1a","year":"2019","journal-title":"J. Biol. Chem."},{"key":"2022051110290501000_JCS259383C14","doi-asserted-by":"publisher","first-page":"9957","DOI":"10.1021\/bi1013936","article-title":"Purification of recombinant Acyl-Coenzyme A:Cholesterol Acyltransferase 1 (ACAT1) from H293 cells and binding studies between the enzyme and substrates using difference intrinsic fluorescence spectroscopy","volume":"49","author":"Chang","year":"2010","journal-title":"Biochemistry"},{"key":"2022051110290501000_JCS259383C15","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nchembio.137","article-title":"Small molecule\u2013mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer","volume":"5","author":"Chen","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"2022051110290501000_JCS259383C16","doi-asserted-by":"publisher","first-page":"3556","DOI":"10.1016\/j.csbj.2021.06.002","article-title":"Leri: a web-server for identifying protein functional networks from evolutionary couplings","volume":"19","author":"Cheung","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2022051110290501000_JCS259383C17","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"2022051110290501000_JCS259383C18","doi-asserted-by":"publisher","first-page":"3357","DOI":"10.1242\/jcs.072132","article-title":"WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification","volume":"123","author":"Coombs","year":"2010","journal-title":"J. Cell Sci."},{"key":"2022051110290501000_JCS259383C19","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/nrg3414","article-title":"Emerging methods in protein co-evolution","volume":"14","author":"de Juan","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"2022051110290501000_JCS259383C20","doi-asserted-by":"publisher","first-page":"W13","DOI":"10.1093\/nar\/gkr245","article-title":"T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension","volume":"39","author":"Di Tommaso","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C21","doi-asserted-by":"publisher","first-page":"e20450","DOI":"10.1371\/journal.pone.0020450","article-title":"Modeling symmetric macromolecular structures in Rosetta3","volume":"6","author":"DiMaio","year":"2011","journal-title":"PLoS ONE"},{"key":"2022051110290501000_JCS259383C22","doi-asserted-by":"publisher","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"2022051110290501000_JCS259383C23","doi-asserted-by":"publisher","first-page":"18598","DOI":"10.1073\/pnas.0904894106","article-title":"Reciprocal regulation of Wnt and Gpr177\/mouse Wntless is required for embryonic axis formation","volume":"106","author":"Fu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022051110290501000_JCS259383C24","doi-asserted-by":"publisher","first-page":"200400","DOI":"10.1098\/rsob.200400","article-title":"Determination of the membrane topology of PORCN, an O-acyl transferase that modifies Wnt signalling proteins","volume":"11","author":"Galli","year":"2021","journal-title":"Open Biol."},{"key":"2022051110290501000_JCS259383C25","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1002\/prot.340180402","article-title":"Correlated mutations and residue contacts in proteins","volume":"18","author":"G\u00f6bel","year":"1994","journal-title":"Proteins"},{"key":"2022051110290501000_JCS259383C26","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1001\/archderm.1992.01680180102015","article-title":"Focal dermal hypoplasia syndrome. An update","volume":"128","author":"Goltz","year":"1992","journal-title":"Arch. Dermatol."},{"key":"2022051110290501000_JCS259383C27","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s10822-010-9349-1","article-title":"Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution","volume":"24","author":"Greenwood","year":"2010","journal-title":"J. Comput. Aid. Mol. Des."},{"key":"2022051110290501000_JCS259383C28","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/ng2052","article-title":"Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia","volume":"39","author":"Grzeschik","year":"2007","journal-title":"Nat. Genet."},{"key":"2022051110290501000_JCS259383C29","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/s41594-019-0216-z","article-title":"Crystal structure of a mammalian Wnt\u2013frizzled complex","volume":"26","author":"Hirai","year":"2019","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2022051110290501000_JCS259383C30","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/S0968-0004(99)01539-X","article-title":"A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling","volume":"25","author":"Hofmann","year":"2000","journal-title":"Trends Biochem. Sci."},{"key":"2022051110290501000_JCS259383C31","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/nature13474","article-title":"Lipid landscapes and pipelines in membrane homeostasis","volume":"510","author":"Holthuis","year":"2014","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C32","doi-asserted-by":"publisher","first-page":"W338","DOI":"10.1093\/nar\/gkv454","article-title":"(PS)2: protein structure prediction server version 3.0","volume":"43","author":"Huang","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1126\/science.1222879","article-title":"Structural basis of Wnt recognition by Frizzled","volume":"337","author":"Janda","year":"2012","journal-title":"Science"},{"key":"2022051110290501000_JCS259383C34","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1016\/S0006-3495(99)77009-8","article-title":"Helix packing in polytopic membrane proteins: role of glycine in transmembrane helix association","volume":"77","author":"Javadpour","year":"1999","journal-title":"Biophys. J."},{"key":"2022051110290501000_JCS259383C35","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1126\/science.abg4998","article-title":"Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT","volume":"372","author":"Jiang","year":"2021","journal-title":"Science"},{"key":"2022051110290501000_JCS259383C36","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/s12276-020-0380-6","article-title":"Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond \u03b2-catenin and the destruction complex","volume":"52","author":"Jung","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"2022051110290501000_JCS259383C37","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/nature14259","article-title":"Notum deacylates Wnt proteins to suppress signalling activity","volume":"519","author":"Kakugawa","year":"2015","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C38","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/978-1-4939-0366-5_2","article-title":"RaptorX server: a resource for template-based protein structure modeling","volume":"1137","author":"K\u00e4llberg","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"2022051110290501000_JCS259383C39","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."},{"key":"2022051110290501000_JCS259383C40","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00439-020-02246-z","article-title":"Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants","volume":"140","author":"Khanna","year":"2021","journal-title":"Hum. Genet."},{"key":"2022051110290501000_JCS259383C41","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nprot.2016.169","article-title":"The ClusPro web server for protein-protein docking","volume":"12","author":"Kozakov","year":"2017","journal-title":"Nat. Protoc."},{"key":"2022051110290501000_JCS259383C42","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1074\/jbc.RA118.005746","article-title":"In vitro reconstitution of Wnt acylation reveals structural determinants of substrate recognition by the acyltransferase human Porcupine","volume":"294","author":"Lee","year":"2019","journal-title":"J. Biol. Chem."},{"key":"2022051110290501000_JCS259383C43","doi-asserted-by":"publisher","first-page":"20224","DOI":"10.1073\/pnas.1314239110","article-title":"Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974","volume":"110","author":"Liu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022051110290501000_JCS259383C44","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.devcel.2016.08.011","article-title":"Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals","volume":"38","author":"Loh","year":"2016","journal-title":"Dev. Cell"},{"key":"2022051110290501000_JCS259383C45","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/s41586-020-2295-8","article-title":"Structure of nevanimibe-bound tetrameric human ACAT1","volume":"581","author":"Long","year":"2020","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C46","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/s41586-018-0568-2","article-title":"Crystal structure of a membrane-bound O-acyltransferase","volume":"562","author":"Ma","year":"2018","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C47","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1038\/onc.2015.280","article-title":"Wnt addiction of genetically defined cancers reversed by PORCN inhibition","volume":"35","author":"Madan","year":"2016","journal-title":"Oncogene"},{"key":"2022051110290501000_JCS259383C48","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ymgmr.2017.06.002","article-title":"A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia","volume":"12","author":"Madan","year":"2017","journal-title":"Mol. Genet. Metab. Rep."},{"key":"2022051110290501000_JCS259383C49","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nchembio.2005","article-title":"Fatty acylation of Wnt proteins","volume":"12","author":"Nile","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"2022051110290501000_JCS259383C50","doi-asserted-by":"publisher","first-page":"4147","DOI":"10.1073\/pnas.1618293114","article-title":"Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding","volume":"114","author":"Nile","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022051110290501000_JCS259383C51","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/j.cell.2017.05.016","article-title":"Wnt\/\u03b2-catenin signaling, disease, and emerging therapeutic modalities","volume":"169","author":"Nusse","year":"2017","journal-title":"Cell"},{"key":"2022051110290501000_JCS259383C52","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.cell.2020.11.038","article-title":"Structural basis of WLS\/Evi-mediated Wnt transport and secretion","volume":"184","author":"Nygaard","year":"2021","journal-title":"Cell"},{"key":"2022051110290501000_JCS259383C53","doi-asserted-by":"publisher","first-page":"e09248","DOI":"10.7554\/eLife.09248","article-title":"Large-scale determination of previously unsolved protein structures using evolutionary information","volume":"4","author":"Ovchinnikov","year":"2015","journal-title":"eLife"},{"key":"2022051110290501000_JCS259383C54","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1109\/TCBB.2015.2459680","article-title":"CAVER: algorithms for analyzing dynamics of tunnels in macromolecules","volume":"13","author":"Pavelka","year":"2016","journal-title":"IEEE\/ACM Trans. Comput. Biol. Bioinform."},{"key":"2022051110290501000_JCS259383C55","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1021\/acs.jcim.5b00159","article-title":"Pharmacophore model for Wnt\/Porcupine inhibitors and its use in drug design","volume":"55","author":"Poulsen","year":"2015","journal-title":"J. Chem. Inf. Model"},{"key":"2022051110290501000_JCS259383C56","doi-asserted-by":"publisher","first-page":"34167","DOI":"10.1074\/jbc.M112.381970","article-title":"Precise regulation of porcupine activity is required for physiological Wnt signaling","volume":"287","author":"Proffitt","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2022051110290501000_JCS259383C57","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1158\/0008-5472.CAN-12-2258","article-title":"Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer","volume":"73","author":"Proffitt","year":"2013","journal-title":"Cancer Res."},{"key":"2022051110290501000_JCS259383C58","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41586-020-2290-0","article-title":"Structural basis for catalysis and substrate specificity of human ACAT1","volume":"581","author":"Qian","year":"2020","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C59","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1038\/s41467-019-09376-7","article-title":"X-ray structures of the high-affinity copper transporter Ctr1","volume":"10","author":"Ren","year":"2019","journal-title":"Nat. Commun."},{"key":"2022051110290501000_JCS259383C60","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/0092-8674(90)90451-J","article-title":"Spatial expression of the Drosophila segment polarity gene armadillo is posttranscriptionally regulated by wingless","volume":"63","author":"Riggleman","year":"1990","journal-title":"Cell"},{"key":"2022051110290501000_JCS259383C61","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/j.celrep.2013.08.027","article-title":"Stearoyl CoA desaturase is required to produce active, lipid-modified Wnt proteins","volume":"4","author":"Rios-Esteves","year":"2013","journal-title":"Cell Rep."},{"key":"2022051110290501000_JCS259383C62","doi-asserted-by":"publisher","first-page":"17009","DOI":"10.1074\/jbc.M114.561209","article-title":"Identification of key residues and regions important for porcupine-mediated Wnt acylation","volume":"289","author":"Rios-Esteves","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2022051110290501000_JCS259383C63","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/S0959-440X(97)80027-9","article-title":"Advances in comparative protein-structure modelling","volume":"7","author":"S\u00e1nchez","year":"1997","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2022051110290501000_JCS259383C64","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput. Aid. Mol. Des."},{"key":"2022051110290501000_JCS259383C65","doi-asserted-by":"publisher","first-page":"105532","DOI":"10.1016\/j.phrs.2021.105532","article-title":"Porcupine inhibitors: novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway","volume":"167","author":"Shah","year":"2021","journal-title":"Pharmacol. Res."},{"key":"2022051110290501000_JCS259383C66","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/s10038-019-0585-5","article-title":"Three additional patients with EED-associated overgrowth: potential mutation hotspots identified?","volume":"64","author":"Spellicy","year":"2019","journal-title":"J. Hum. Genet."},{"key":"2022051110290501000_JCS259383C67","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/s41586-020-2289-6","article-title":"Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme","volume":"581","author":"Sui","year":"2020","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C68","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1016\/j.devcel.2006.10.003","article-title":"Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion","volume":"11","author":"Takada","year":"2006","journal-title":"Dev. Cell"},{"key":"2022051110290501000_JCS259383C69","doi-asserted-by":"publisher","first-page":"4300","DOI":"10.1046\/j.1432-1033.2000.01478.x","article-title":"The evolutionarily conserved porcupine gene family is involved in the processing of the Wnt family","volume":"267","author":"Tanaka","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"2022051110290501000_JCS259383C70","doi-asserted-by":"publisher","first-page":"6273","DOI":"10.1074\/jbc.RA118.007268","article-title":"Stereoselective fatty acylation is essential for the release of lipidated WNT proteins from the acyltransferase Porcupine (PORCN)","volume":"294","author":"Tuladhar","year":"2019","journal-title":"J. Biol. Chem."},{"key":"2022051110290501000_JCS259383C71","doi-asserted-by":"publisher","first-page":"5293","DOI":"10.1002\/j.1460-2075.1993.tb06225.x","article-title":"Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein","volume":"12","author":"van den Heuvel","year":"1993","journal-title":"EMBO J."},{"key":"2022051110290501000_JCS259383C72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/0250-474X.102537","article-title":"Homology modeling a fast tool for drug discovery: current perspectives","volume":"74","author":"Vyas","year":"2012","journal-title":"Indian J. Pharm. Sci."},{"key":"2022051110290501000_JCS259383C73","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/ng2057","article-title":"Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia","volume":"39","author":"Wang","year":"2007","journal-title":"Nat. Genet."},{"key":"2022051110290501000_JCS259383C74","doi-asserted-by":"publisher","first-page":"2700","DOI":"10.1021\/jm400159c","article-title":"The development of highly potent inhibitors for porcupine","volume":"56","author":"Wang","year":"2013","journal-title":"J. Med. Chem."},{"key":"2022051110290501000_JCS259383C75","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-020-2280-2","article-title":"Structure and mechanism of human diacylglycerol O-acyltransferase 1","volume":"581","author":"Wang","year":"2020","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C76","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C77","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1002\/ajmg.a.61938","article-title":"Non-syndromic anophthalmia\/microphthalmia can be caused by a PORCN variant inherited in X-linked recessive manner","volume":"185","author":"Wawrocka","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"2022051110290501000_JCS259383C78","doi-asserted-by":"publisher","first-page":"5.6.1","DOI":"10.1002\/cpbi.3","article-title":"Comparative protein structure modeling using MODELLER","volume":"54","author":"Webb","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"2022051110290501000_JCS259383C79","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/nature08142","article-title":"Biophysical dissection of membrane proteins","volume":"459","author":"White","year":"2009","journal-title":"Nature"},{"key":"2022051110290501000_JCS259383C80","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/S0092-8674(04)00216-8","article-title":"Vascular development in the retina and inner ear control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair","volume":"116","author":"Xu","year":"2004","journal-title":"Cell"},{"key":"2022051110290501000_JCS259383C81","doi-asserted-by":"publisher","first-page":"5.8.1","DOI":"10.1002\/0471250953.bi0508s52","article-title":"Protein structure and function prediction using I-TASSER","volume":"52","author":"Yang","year":"2015","journal-title":"Curr. Protoc. Bioinform."},{"key":"2022051110290501000_JCS259383C82","doi-asserted-by":"publisher","first-page":"W174","DOI":"10.1093\/nar\/gkv342","article-title":"I-TASSER server: new development for protein structure and function predictions","volume":"43","author":"Yang","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2022051110290501000_JCS259383C83","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1073\/pnas.1914677117","article-title":"Improved protein structure prediction using predicted interresidue orientations","volume":"117","author":"Yang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022051110290501000_JCS259383C84","doi-asserted-by":"publisher","first-page":"e00142","DOI":"10.1042\/BSR20140119","article-title":"Updating the Wnt pathways","volume":"34","author":"Yu","year":"2014","journal-title":"Biosci. Rep."},{"key":"2022051110290501000_JCS259383C85","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.devcel.2014.03.016","article-title":"WLS retrograde transport to the endoplasmic reticulum during Wnt secretion","volume":"29","author":"Yu","year":"2014","journal-title":"Dev. Cell"},{"key":"2022051110290501000_JCS259383C89","doi-asserted-by":"publisher","DOI":"10.5061\/dryad.crjdfn35j","article-title":"Structural model of PORCN .cif and .pdb files","author":"Yu","year":"2021","journal-title":"Dryad Digital Repository"},{"key":"2022051110290501000_JCS259383C86","doi-asserted-by":"publisher","first-page":"5619","DOI":"10.1158\/0008-5472.CAN-20-0957","article-title":"The functional landscape of patient-derived RNF43 mutations predicts sensitivity to Wnt inhibition","volume":"80","author":"Yu","year":"2020","journal-title":"Cancer Res."},{"key":"2022051110290501000_JCS259383C87","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1124\/mol.119.117978","article-title":"Wnt signaling and drug resistance in cancer","volume":"97","author":"Zhong","year":"2020","journal-title":"Mol. Pharmacol."},{"key":"2022051110290501000_JCS259383C88","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/s10555-020-09887-6","article-title":"Wnts and the hallmarks of cancer","volume":"39","author":"Zhong","year":"2020","journal-title":"Cancer Metast. Rev."}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.259383\/2120621\/jcs259383.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.259383\/2142082\/jcs259383.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.259383\/2142082\/jcs259383.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T06:29:22Z","timestamp":1652250562000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/134\/24\/jcs259383\/273795\/Structural-model-of-human-PORCN-illuminates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,15]]},"references-count":89,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2021,12,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.259383","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.07.19.452875","asserted-by":"object"}]},"ISSN":["0021-9533","1477-9137"],"issn-type":[{"value":"0021-9533","type":"print"},{"value":"1477-9137","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,15]]},"article-number":"jcs259383"}}