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=== Structure === {{Further|Major prion protein#Structure}} Prions consist of a misfolded form of [[major prion protein]] (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different [[Protein structure|structure]] and is resistant to [[protease]]s, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrP<sup>C</sup>, while the infectious form is called PrP<sup>Sc</sup> – the ''C'' refers to 'cellular' PrP, while the ''Sc'' refers to '[[scrapie]]', the prototypic prion disease, occurring in sheep.<ref name="sci5621">{{cite journal | vauthors = Priola SA, Chesebro B, Caughey B | title = Biomedicine. A view from the top--prion diseases from 10,000 feet | journal = Science | volume = 300 | issue = 5621 | pages = 917–9 | date = May 2003 | pmid = 12738843 | doi = 10.1126/science.1085920 | url = https://zenodo.org/record/1230830 | access-date = 2020-07-28 | url-status = live | s2cid = 38459669 | archive-url = https://web.archive.org/web/20200728140633/https://zenodo.org/record/1230830 | archive-date = 2020-07-28 }}</ref> PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.<ref>{{cite journal | vauthors = Artikis E, Kraus A, Caughey B | title = Structural biology of ex vivo mammalian prions | journal = The Journal of Biological Chemistry | volume = 298 | issue = 8 | pages = 102181 | date = August 2022 | pmid = 35752366 | pmc = 9293645 | doi = 10.1016/j.jbc.2022.102181 | doi-access = free }}</ref> ==== PrP<sup>C</sup> ==== PrP<sup>C</sup> is a normal protein found on the [[cell membrane|membranes]] of [[cell (biology)|cells]], "including several blood components of which [[platelets]] constitute the largest reservoir in humans."<ref name="robertson06">{{cite journal | vauthors = Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A | title = Cellular prion protein is released on exosomes from activated platelets | journal = Blood | volume = 107 | issue = 10 | pages = 3907–11 | date = May 2006 | pmid = 16434486 | doi = 10.1182/blood-2005-02-0802 | s2cid = 34141310 | doi-access = free }}</ref> It has 209 [[amino acid]]s (in humans), one [[disulfide bond]], a molecular mass of 35–36 [[Atomic mass unit|kDa]] and a mainly [[alpha helix|alpha-helical]] structure.<ref>{{cite journal | vauthors = Riek R, Hornemann S, Wider G, Glockshuber R, Wüthrich K | title = NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231) | journal = FEBS Letters | volume = 413 | issue = 2 | pages = 282–8 | date = August 1997 | pmid = 9280298 | doi = 10.1016/S0014-5793(97)00920-4 | s2cid = 39791520 | bibcode = 1997FEBSL.413..282R | url = https://www.zora.uzh.ch/id/eprint/191727/1/S0014-5793%2897%2900920-4.pdf }}</ref><ref>{{cite journal | vauthors = Donne DG, Viles JH, Groth D, Mehlhorn I, James TL, Cohen FE, Prusiner SB, Wright PE, Dyson HJ | title = Structure of the recombinant full-length hamster prion protein PrP(29-231): the N terminus is highly flexible | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 25 | pages = 13452–7 | date = December 1997 | pmid = 9391046 | pmc = 28326 | doi = 10.1073/pnas.94.25.13452 | doi-access = free | bibcode = 1997PNAS...9413452D }}</ref> Several [[Protein topology|topological]] forms exist; one cell surface form anchored via [[glycolipid]] and two [[transmembrane]] forms.<ref>{{cite journal | vauthors = Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond SJ, Prusiner SB, Lingappa VR | title = A transmembrane form of the prion protein in neurodegenerative disease | journal = Science | volume = 279 | issue = 5352 | pages = 827–834 | date = February 1998 | pmid = 9452375 | doi = 10.1126/science.279.5352.827 | url = http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | url-status = dead | s2cid = 20176119 | bibcode = 1998Sci...279..827H | archive-url = https://web.archive.org/web/20190223062543/http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | archive-date = 2019-02-23 }}</ref> The normal protein is not sedimentable; meaning that it cannot be separated by [[Laboratory centrifuge|centrifuging techniques]].<ref name=Krull>{{cite book | vauthors = Carp RI, Kascap RJ | chapter = Taking aim at the transmissible spongiform encephalopathie's infectious agents | veditors = Krull IS, Nunnally BK | title = Prions and mad cow disease | publisher = Marcel Dekker | location = New York | year = 2004 | page = 6 | isbn = 978-0-8247-4083-2 | chapter-url = https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | access-date = 2020-06-02 | archive-date = 2020-08-20 | archive-url = https://web.archive.org/web/20200820011006/https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | url-status = live }}</ref> It has a complex [[Protein function|function]], which continues to be investigated. PrP<sup>C</sup> [[Chemical bond|binds]] [[copper]](II) [[ion]]s (those in a +2 [[oxidation state]]) with [[high affinity]].<ref>{{cite journal | vauthors = Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H | title = The cellular prion protein binds copper in vivo | journal = Nature | volume = 390 | issue = 6661 | pages = 684–7 | year = 1997 | pmid = 9414160 | doi = 10.1038/37783 | s2cid = 4388803 | bibcode = 1997Natur.390..684B }}</ref> This property is supposed to play a role in PrP<sup>C</sup>’s [[anti-oxidative]] properties via reversible [[oxidation]] of the [[Protein structure|N-terminal’s]] [[methionine]] residues into [[sulfoxide]].<ref>{{cite journal |last1=Arcos-López |first1=Trinidad |title=Spectroscopic and Theoretical Study of CuI Binding to His111 in the Human Prion Protein Fragment 106–115 |journal=Organic Chemistry 2016 |date=1 March 2016 |volume=55 |issue=Inorganic Chemistry 2016 |pages=2909–22 |doi=10.1021/acs.inorgchem.5b02794 |pmid=26930130 |pmc=4804749 |hdl=11336/52826 |hdl-access=free }}</ref> Moreover, studies have suggested that, [[in vivo]], due to PrP<sup>C</sup>’s low [[Binding selectivity|selectivity]] to metallic substrates, the protein’s anti oxidative function is impaired when in contact with metals other than [[copper]].<ref>{{cite journal |last1=Wong |first1=Boon-Seng |title=A Yin-Yang role for metals in prion disease |journal=Panminerva Medica (2001) |date=December 2001 |volume=43 |issue=4 |pages=283–7 |pmid=11677424 |url=https://pubmed.ncbi.nlm.nih.gov/11677424/ |access-date=12 November 2024}}</ref> PrP<sup>C</sup> is readily [[Digestion|digested]] by [[proteinase K]] and can be [[Exocytosis|liberated]] from the cell surface by the enzyme [[phospholipase C|phosphoinositide phospholipase C]] (PI-PLC), which [[Bond cleavage|cleaves]] the [[glycophosphatidylinositol]] (GPI) glycolipid anchor.<ref name="weissmann">{{cite journal | vauthors = Weissmann C | title = The state of the prion | journal = Nature Reviews. Microbiology | volume = 2 | issue = 11 | pages = 861–871 | date = November 2004 | pmid = 15494743 | doi = 10.1038/nrmicro1025 | s2cid = 20992257 }}</ref> PrP plays an important role in [[cell-cell adhesion]] and [[intracellular signaling]] ''in vivo'',<ref>{{cite journal | vauthors = Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, Stuermer CA | title = Regulation of embryonic cell adhesion by the prion protein | journal = PLOS Biology | volume = 7 | issue = 3 | pages = e55 | date = March 2009 | pmid = 19278297 | pmc = 2653553 | doi = 10.1371/journal.pbio.1000055 | veditors = Weissmann C | doi-access = free }}</ref> and may therefore be involved in cell-cell communication in the brain.<ref>{{Cite journal | vauthors = Liebert A, Bicknell B, Adams R |date=2014 |title=Prion Protein Signaling in the Nervous System—A Review and Perspective |journal=Signal Transduction Insights |language=en |volume=3 |pages=STI.S12319 |doi=10.4137/STI.S12319 |issn=1178-6434|doi-access=free }}</ref> ==== PrP<sup>Sc</sup> ==== [[File:Scrapie prions.jpg|alt=Photomicrograph of mouse neurons showing red stained inclusions identified as scrapies prion protein.|thumb|upright=0.8|PrP<sup>Sc</sup> (stained in red) revealed in a photomicrograph of scrapie-infected mouse neuronal cells.]] The infectious [[isoform]] of PrP, known as PrP<sup>Sc</sup>, or simply the prion, is able to convert normal PrP<sup>C</sup> proteins into the infectious isoform by changing their [[Protein structure|conformation]], or shape; this, in turn, alters the way the proteins [[Protein–protein interaction|interconnect]]. PrP<sup>Sc</sup> always causes prion disease. PrP<sup>Sc</sup> has a higher proportion of [[beta sheet|β-sheet]] structure in place of the normal [[alpha helix|α-helix]] structure.<ref>{{cite journal | vauthors = Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, Caughey WS | title = Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy | journal = Biochemistry | volume = 30 | issue = 31 | pages = 7672–80 | date = August 1991 | pmid = 1678278 | doi = 10.1021/bi00245a003 }}</ref><ref>{{cite journal | vauthors = Safar J, Roller PP, Gajdusek DC, Gibbs CJ | title = Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein | journal = The Journal of Biological Chemistry | volume = 268 | issue = 27 | pages = 20276–84 | date = September 1993 | pmid = 8104185 | doi = 10.1016/s0021-9258(20)80725-x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE | title = Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 10962–6 | date = December 1993 | pmid = 7902575 | pmc = 47901 | doi = 10.1073/pnas.90.23.10962 | doi-access = free | bibcode = 1993PNAS...9010962P }}</ref> Several highly infectious, brain-derived PrP<sup>Sc</sup> structures have been discovered by [[cryo-electron microscopy]].<ref name=Kraus21>{{cite journal | vauthors = Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, Raymond GJ, Race B, Baron GS, Caughey B | title = High-resolution structure and strain comparison of infectious mammalian prions | journal = Molecular Cell | volume = 81 | issue = 21 | pages = 4540–51 | date = November 2021 | pmid = 34433091 | doi = 10.1016/j.molcel.2021.08.011 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A | title = Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains | journal = Nature Communications | volume = 13 | issue = 1 | pages = 4005 | date = July 2022 | pmid = 35831291 | pmc = 9279418 | doi = 10.1038/s41467-022-30458-6 | bibcode = 2022NatCo..13.4005H }}</ref><ref>{{cite journal | vauthors = Manka SW, Zhang W, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = 2.7 Å cryo-EM structure of ex vivo RML prion fibrils | journal = Nature Communications | volume = 13 | issue = 1 | pages = 4004 | date = July 2022 | pmid = 35831275 | pmc = 9279362 | doi = 10.1038/s41467-022-30457-7 | bibcode = 2022NatCo..13.4004M }}</ref> Another brain-derived [[fibril]] structure isolated from humans with [[Gerstmann–Sträussler–Scheinker syndrome|Gerstmann-Straussler-Schienker syndrome]] has also been determined.<ref>{{cite journal | vauthors = Hallinan GI, Ozcan KA, Hoq MR, Cracco L, Vago FS, Bharath SR, Li D, Jacobsen M, Doud EH, Mosley AL, Fernandez A, Garringer HJ, Jiang W, Ghetti B, Vidal R | title = Cryo-EM structures of prion protein filaments from Gerstmann-Sträussler-Scheinker disease | journal = Acta Neuropathologica | volume = 144 | issue = 3 | pages = 509–520 | date = September 2022 | pmid = 35819518 | pmc = 9381446 | doi = 10.1007/s00401-022-02461-0 }}</ref> All of the structures described in high resolution so far are [[amyloid]] fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D [[Crystalline form|crystalline arrays]] have also been reported at lower resolution in ''ex vivo'' preparations of prions.<ref>{{cite journal | vauthors = Wille H, Michelitsch MD, Guenebaut V, Supattapone S, Serban A, Cohen FE, Agard DA, Prusiner SB | title = Structural studies of the scrapie prion protein by electron crystallography | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 6 | pages = 3563–8 | date = March 2002 | pmid = 11891310 | pmc = 122563 | doi = 10.1073/pnas.052703499 | doi-access = free | bibcode = 2002PNAS...99.3563W }}</ref> In the prion amyloids, the [[glycolipid]] anchors and [[asparagine]]-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrP<sup>Sc</sup> is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrP<sup>C</sup>.<ref name=Kraus21/> Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same [[amino acid sequence]], as occurs in a particular host [[genotype]].<ref>{{cite journal | vauthors = Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B | title = Non-genetic propagation of strain-specific properties of scrapie prion protein | journal = Nature | volume = 375 | issue = 6533 | pages = 698–700 | date = June 1995 | pmid = 7791905 | doi = 10.1038/375698a0 | s2cid = 4355092 | bibcode = 1995Natur.375..698B }}</ref><ref>{{cite journal | vauthors = Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB | title = Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity | journal = Science | volume = 274 | issue = 5295 | pages = 2079–82 | date = December 1996 | pmid = 8953038 | doi = 10.1126/science.274.5295.2079 | bibcode = 1996Sci...274.2079T }}</ref><ref>{{cite journal | vauthors = Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB | title = Eight prion strains have PrP(Sc) molecules with different conformations | journal = Nature Medicine | volume = 4 | issue = 10 | pages = 1157–65 | date = October 1998 | pmid = 9771749 | doi = 10.1038/2654 | s2cid = 6031488 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Alam P, Artikis E, Schwartz CL, Hughson AG, Race B, Baune C, Raymond GJ, Baron GS, Kraus A, Caughey B | title = Cryo-EM of prion strains from the same genotype of host identifies conformational determinants | journal = PLOS Pathogens | volume = 18 | issue = 11 | pages = e1010947 | date = November 2022 | pmid = 36342968 | pmc = 9671466 | doi = 10.1371/journal.ppat.1010947 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Manka SW, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = A structural basis for prion strain diversity | journal = Nature Chemical Biology | volume = 19 | issue = 5 | pages = 607–613 | date = May 2023 | pmid = 36646960 | pmc = 10154210 | doi = 10.1038/s41589-022-01229-7 }}</ref> Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP<sup>Sc</sup> are incorporated into the growing fiber.<ref name=Krull /> However, [[cross-species transmission]] also happens rarely.<ref name="pmid26809254">{{cite journal | vauthors = Kurt TD, Sigurdson CJ | title = Cross-species transmission of CWD prions | journal = Prion | volume = 10 | issue = 1 | pages = 83–91 | date = 2016 | pmid = 26809254 | pmc = 4981193 | doi = 10.1080/19336896.2015.1118603 }}</ref> ==== PrP<sup>res</sup> ==== Protease-resistant PrP<sup>Sc</sup>-like protein (PrP<sup>res</sup>) is the name given to any isoform of PrP<sup>c</sup> which is structurally altered and converted into a misfolded [[proteinase K]]-resistant form.<ref>{{cite journal | vauthors = Riesner D | title = Biochemistry and structure of PrP(C) and PrP(Sc) | journal = British Medical Bulletin | volume = 66 | issue = 1 | pages = 21–33 | date = June 2003 | pmid = 14522846 | doi = 10.1093/bmb/66.1.21 | doi-access = free }}</ref> To model conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> ''in vitro'', Kocisko ''et al''. showed that PrP<sup>Sc</sup> could cause PrP<sup>C</sup> to convert to PrP<sup>res</sup> under cell-free conditions <ref name="pmid7913989">{{cite journal | vauthors = Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, Caughey B | title = Cell-free formation of protease-resistant prion protein | journal = Nature | volume = 370 | issue = 6489 | pages = 471–4 | date = August 1994 | pmid = 7913989 | doi = 10.1038/370471a0 | bibcode = 1994Natur.370..471K | hdl-access = free | s2cid = 4337709 | hdl = 1721.1/42578 }}</ref> and Soto ''et al''. demonstrated sustained amplification of PrP<sup>res</sup> and prion infectivity by a procedure involving [[Protein misfolding cyclic amplification|cyclic amplification of protein misfolding]].<ref name="pmid11459061">{{cite journal | vauthors = Saborio GP, Permanne B, Soto C | title = Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding | journal = Nature | volume = 411 | issue = 6839 | pages = 810–3 | date = June 2001 | pmid = 11459061 | doi = 10.1038/35081095 | bibcode = 2001Natur.411..810S | s2cid = 4317585 }}</ref> The term "PrP<sup>res</sup>" may refer either to protease-resistant forms of PrP<sup>Sc</sup>, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated ''in vitro''.<ref name="pmid15297610">{{cite journal | vauthors = Bieschke J, Weber P, Sarafoff N, Beekes M, Giese A, Kretzschmar H | title = Autocatalytic self-propagation of misfolded prion protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12207–11 | date = August 2004 | pmid = 15297610 | pmc = 514458 | doi = 10.1073/pnas.0404650101 | bibcode = 2004PNAS..10112207B | doi-access = free }}</ref> Accordingly, unlike PrP<sup>Sc</sup>, PrP<sup>res</sup> may not necessarily be infectious. [[File:Prion structure membrane bound fibril.jpg|thumb|Models of normal (PrP<sup>C</sup>) and infectious (PrP<sup>Sc</sup>) forms of prion protein on a membrane: polypeptide (turquoise); glycans (red); glycolipid anchors (blue). The core structures are based on NMR spectroscopy (PrP<sup>C</sup>) and cryo-electron microscopy (PrP<sup>Sc</sup>).]]
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