{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:12:56Z","timestamp":1791191576206,"version":"4.1.0"},"reference-count":48,"publisher":"Portland Press Ltd.","issue":"6","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,12,1]]},"abstract":"<jats:p>The cellular form of the prion protein, PrPc, is critically required for the establishment of prion diseases, such as Creutzfeldt\u2013Jakob disease. Within the N-terminal half of PrPc are four octapeptide repeats that bind Cu2+. Exposure of neuronal cells expressing PrPc to Cu2+ results in the rapid endocytosis of the protein. First, PrPc translocates laterally out of detergent-resistant lipid rafts into detergent-soluble regions of the plasma membrane, then it is internalized through clathrin-coated pits. The extreme N-terminal region of PrPc is critically required for its endocytosis, as is the transmembrane LRP1 (low-density lipoprotein receptor-related protein-1). Incubation of cells with a competitive inhibitor of LRP1 ligands, receptor-associated protein, or down-regulation of LRP1 with siRNA (short interfering RNA) reduces the endocytosis of PrPc. Zn2+ also promotes the endocytosis of PrPc, a phenomenon that is also dependent on the octapeptide repeats and requires LRP1.<\/jats:p>","DOI":"10.1042\/bst0361272","type":"journal-article","created":{"date-parts":[[2008,12,2]],"date-time":"2008-12-02T17:27:13Z","timestamp":1228238833000},"page":"1272-1276","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Mechanism of the metal-mediated endocytosis of the prion protein"],"prefix":"10.1042","volume":"36","author":[{"given":"Nigel\u00a0M.","family":"Hooper","sequence":"first","affiliation":[{"name":"Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K., and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David\u00a0R.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K., and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole\u00a0T.","family":"Watt","sequence":"additional","affiliation":[{"name":"Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K., and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2008,11,19]]},"reference":[{"key":"2021111720383978200_B1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S1471-4914(03)00069-8","article-title":"Is loss of function of the prion protein the cause of prion disorders?","volume":"9","author":"Hetz","year":"2003","journal-title":"Trends Mol. Med."},{"key":"2021111720383978200_B2","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1046\/j.1471-4159.2003.01882.x","article-title":"Cellular prion protein function in copper homeostasis and redox signalling at the synapse","volume":"86","author":"Vassallo","year":"2003","journal-title":"J. Neurochem."},{"key":"2021111720383978200_B3","doi-asserted-by":"crossref","first-page":"35914","DOI":"10.1074\/jbc.M507327200","article-title":"Reactive oxygen species-mediated \u03b2-cleavage of the prion protein in the cellular response to oxidative stress","volume":"280","author":"Watt","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B4","doi-asserted-by":"crossref","first-page":"11062","DOI":"10.1073\/pnas.0609621104","article-title":"Cellular prion protein regulates \u03b2-secretase cleavage of the Alzheimer's amyloid precursor protein","volume":"104","author":"Parkin","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111720383978200_B5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/09687860500449994","article-title":"The prion protein and lipid rafts","volume":"23","author":"Taylor","year":"2006","journal-title":"Mol. Membr. Biol."},{"key":"2021111720383978200_B6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1073\/pnas.97.1.145","article-title":"NMR solution structure of the human prion protein","volume":"97","author":"Zahn","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111720383978200_B7","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1073\/pnas.96.5.2042","article-title":"Copper binding to the prion protein: structural implications of four identical cooperative binding sites","volume":"96","author":"Viles","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111720383978200_B8","doi-asserted-by":"crossref","first-page":"7185","DOI":"10.1021\/bi972827k","article-title":"Prion protein selectively binds copper(II) ions","volume":"37","author":"Stockel","year":"1998","journal-title":"Biochemistry"},{"key":"2021111720383978200_B9","doi-asserted-by":"crossref","first-page":"33107","DOI":"10.1074\/jbc.273.50.33107","article-title":"Copper stimulates endocytosis of the prion protein","volume":"273","author":"Pauly","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B10","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0960-9822(01)00147-6","article-title":"Ablation of the metal ion-induced endocytosis of the prion protein by disease-associated mutation of the octarepeat region","volume":"11","author":"Perera","year":"2001","journal-title":"Curr. Biol."},{"key":"2021111720383978200_B11","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0169-328X(95)00175-R","article-title":"Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene","volume":"34","author":"Krasemann","year":"1995","journal-title":"Mol. Brain Res."},{"key":"2021111720383978200_B12","doi-asserted-by":"crossref","first-page":"25457","DOI":"10.1074\/jbc.M203248200","article-title":"Filipin prevents pathological prion protein accumulation by reducing endocytosis and inducing cellular PrP release","volume":"277","author":"Marella","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B13","doi-asserted-by":"crossref","first-page":"11170","DOI":"10.1074\/jbc.M312105200","article-title":"Dual mechanisms for shedding of the cellular prion protein","volume":"279","author":"Parkin","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B14","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1083\/jcb.200304140","article-title":"Trafficking of prion proteins through a caveolae-mediated endosomal pathway","volume":"162","author":"Peters","year":"2003","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B15","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1083\/jcb.129.3.619","article-title":"Glycolipid-anchored proteins in neuroblastoma cells form detergent-resistant complexes without caveolin","volume":"129","author":"Gorodinsky","year":"1995","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B16","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1046\/j.1471-4159.1997.69052179.x","article-title":"The amyloid precursor protein is not enriched in caveolae-like, detergent-insoluble membrane microdomains","volume":"69","author":"Parkin","year":"1997","journal-title":"J. Neurochem."},{"key":"2021111720383978200_B17","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1083\/jcb.125.6.1239","article-title":"A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits","volume":"125","author":"Shyng","year":"1994","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B18","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.1093\/emboj\/cdg344","article-title":"The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein","volume":"22","author":"Sunyach","year":"2003","journal-title":"EMBO J."},{"key":"2021111720383978200_B19","doi-asserted-by":"crossref","first-page":"12022","DOI":"10.1074\/jbc.M211966200","article-title":"Tyrphostin A23 inhibits internalization of the transferrin receptor by perturbing the interaction between tyrosine motifs and the medium chain subunit of the AP-2 adaptor complex","volume":"278","author":"Banbury","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B20","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1126\/science.291.5506.1051","article-title":"Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes","volume":"291","author":"Ford","year":"2001","journal-title":"Science"},{"key":"2021111720383978200_B21","doi-asserted-by":"crossref","first-page":"5141","DOI":"10.1242\/jcs.02627","article-title":"Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis","volume":"118","author":"Taylor","year":"2005","journal-title":"J. Cell Sci."},{"key":"2021111720383978200_B22","doi-asserted-by":"crossref","first-page":"30636","DOI":"10.1074\/jbc.274.43.30636","article-title":"Regulated migration of epidermal growth factor receptor from caveolae","volume":"274","author":"Mineo","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1083\/jcb.200211018","article-title":"Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process","volume":"160","author":"Abrami","year":"2003","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B24","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1083\/jcb.108.4.1331","article-title":"Endocytosis from coated pits of Shiga toxin: a glycolipid-binding protein from Shigella dysenteriae 1","volume":"108","author":"Sandvig","year":"1989","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B25","doi-asserted-by":"crossref","first-page":"9182","DOI":"10.1074\/jbc.M009414200","article-title":"Cholera toxin is found in detergent-insoluble rafts\/domains at the cell surface of hippocampal neurons but is internalized via a raft-independent mechanism","volume":"276","author":"Shogomori","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B26","doi-asserted-by":"crossref","first-page":"6917","DOI":"10.1093\/emboj\/18.24.6917","article-title":"Functionally different GPI proteins are organised in different domains on the neuronal surface","volume":"19","author":"Madore","year":"1999","journal-title":"EMBO J."},{"key":"2021111720383978200_B27","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.jmb.2003.09.048","article-title":"The octapeptide repeats in mammalian prion protein constitute a pH-dependent folding and aggregation site","volume":"334","author":"Zahn","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2021111720383978200_B28","doi-asserted-by":"crossref","first-page":"11753","DOI":"10.1074\/jbc.M312860200","article-title":"Inter- and intra-octarepeat Cu(II) site geometries in the prion protein: implications in Cu(II) binding cooperativity and Cu(II)-mediated assemblies","volume":"279","author":"Morante","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B29","doi-asserted-by":"crossref","first-page":"37241","DOI":"10.1074\/jbc.M302036200","article-title":"The N-terminal region of the prion protein ectodomain contains a lipid raft targeting determinant","volume":"278","author":"Walmsley","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B30","doi-asserted-by":"crossref","first-page":"14883","DOI":"10.1074\/jbc.M210840200","article-title":"Effect of glycosylphosphatidylinositol anchor-dependent and -independent prion protein association with model raft membranes on conversion to the protease-resistant isoform","volume":"278","author":"Baron","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B31","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/j.1398-9219.2004.00185.x","article-title":"Misfolding of the prion protein at the plasma membrane induces endocytosis, intracellular retention and degradation","volume":"5","author":"Kiachopoulos","year":"2004","journal-title":"Traffic"},{"key":"2021111720383978200_B32","doi-asserted-by":"crossref","first-page":"3726","DOI":"10.1074\/jbc.M206313200","article-title":"Essential role of the prion protein N terminus in subcellular trafficking and half-life of cellular prion protein","volume":"278","author":"Nunziante","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B33","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.1093\/emboj\/cdf325","article-title":"Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection","volume":"21","author":"Zanata","year":"2002","journal-title":"EMBO J."},{"key":"2021111720383978200_B34","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1006\/jmbi.2000.5183","article-title":"Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein","volume":"314","author":"Schmitt-Ulms","year":"2001","journal-title":"J. Mol. Biol."},{"key":"2021111720383978200_B35","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1083\/jcb.200409127","article-title":"Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth","volume":"169","author":"Santuccione","year":"2005","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B36","doi-asserted-by":"crossref","first-page":"5876","DOI":"10.1093\/emboj\/20.21.5876","article-title":"Identification of interaction domains of the prion protein with its 37-kDa\/67-kDa laminin receptor","volume":"20","author":"Hundt","year":"2001","journal-title":"EMBO J."},{"key":"2021111720383978200_B37","doi-asserted-by":"crossref","first-page":"5863","DOI":"10.1093\/emboj\/20.21.5863","article-title":"The 37-kDa\/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein","volume":"20","author":"Gauczynski","year":"2001","journal-title":"EMBO J."},{"key":"2021111720383978200_B38","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s001090050356","article-title":"The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism","volume":"77","author":"Willnow","year":"1999","journal-title":"J. Mol. Med."},{"key":"2021111720383978200_B39","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0962-8924(02)02282-1","article-title":"The low-density lipoprotein receptor gene family: a cellular Swiss army knife?","volume":"12","author":"Nykjaer","year":"2002","journal-title":"Trends Cell Biol."},{"key":"2021111720383978200_B40","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/S1043-2760(01)00526-4","article-title":"Diverse roles for the LDL receptor family","volume":"13","author":"Strickland","year":"2002","journal-title":"Trends Endocrinol. Metab."},{"key":"2021111720383978200_B41","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/00041433-199804000-00012","article-title":"Receptor-associated protein: a specialized chaperone and antagonist for members of the LDL receptor gene family","volume":"9","author":"Bu","year":"1998","journal-title":"Curr. Opin. Lipidol."},{"key":"2021111720383978200_B42","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/BJ20061736","article-title":"The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein","volume":"402","author":"Taylor","year":"2007","journal-title":"Biochem. J."},{"key":"2021111720383978200_B43","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1242\/jcs.021816","article-title":"LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein","volume":"121","author":"Parkyn","year":"2008","journal-title":"J. Cell Sci."},{"key":"2021111720383978200_B44","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1001\/archneur.57.5.646","article-title":"Role of the low-density lipoprotein receptor-related protein in \u03b2-amyloid metabolism and Alzheimer disease","volume":"57","author":"Hyman","year":"2000","journal-title":"Arch. Neurol."},{"key":"2021111720383978200_B45","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.1093\/emboj\/cdf568","article-title":"The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing","volume":"21","author":"Pietrzik","year":"2002","journal-title":"EMBO J."},{"key":"2021111720383978200_B46","doi-asserted-by":"crossref","first-page":"14543","DOI":"10.1016\/S0021-9258(18)42072-8","article-title":"Purified \u03b12-macroglobulin receptor\/LDL receptor-related protein binds urokinase\u00b7plasminogen activator inhibitor type-1 complex: evidence that the \u03b12-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes","volume":"267","author":"Nykjaer","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2021111720383978200_B47","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1083\/jcb.129.2.335","article-title":"The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae","volume":"129","author":"Stahl","year":"1995","journal-title":"J. Cell Biol."},{"key":"2021111720383978200_B48","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1002\/jcb.20596","article-title":"The low-density lipoprotein receptor-related protein-1 associates transiently with lipid rafts","volume":"96","author":"Wu","year":"2005","journal-title":"J. Cell. Biochem."}],"container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/36\/6\/1272\/852807\/bst0361272.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/36\/6\/1272\/852807\/bst0361272.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:55:25Z","timestamp":1637196925000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/36\/6\/1272\/66549\/Mechanism-of-the-metal-mediated-endocytosis-of-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11,19]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2008,11,19]]},"published-print":{"date-parts":[[2008,12,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bst0361272","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"value":"0300-5127","type":"print"},{"value":"1470-8752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,11,19]]}}}