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{{short description|Protein involved in multiple prion diseases}}
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{{Distinguish|Prion|text=[[prion]]s, infectious forms of proteins which have so far been observed in almost all instances to be forms of PRNP, but need not be}}
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{{Infobox_gene}}
The '''major prion protein''' ('''PrP''') is encoded in the human body by the ''PRNP'' [[gene]] also known as '''CD230''' ([[cluster of differentiation]] 230).<ref name = "pmid3755672">{{cite journal | vauthors = Kretzschmar HA, Stowring LE, Westaway D, Stubblebine WH, Prusiner SB, Dearmond SJ | title = Molecular cloning of a human prion protein cDNA | journal = DNA | volume = 5 | issue = 4 | pages = 315–24 | date = August 1986 | pmid = 3755672 | doi = 10.1089/dna.1986.5.315}}</ref><ref name = "pmid3094007">{{cite journal | vauthors = Sparkes RS, Simon M, Cohn VH, Fournier RE, Lem J, Klisak I, Heinzmann C, Blatt C, Lucero M, Mohandas T | title = Assignment of the human and mouse prion protein genes to homologous chromosomes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 83 | issue = 19 | pages = 7358–62 | date = October 1986 | pmid = 3094007 | pmc = 386716 | doi = 10.1073/pnas.83.19.7358 | bibcode = 1986PNAS...83.7358S | doi-access = free }}</ref><ref name = "pmid3014653">{{cite journal | vauthors = Liao YC, Lebo RV, Clawson GA, Smuckler EA | title = Human prion protein cDNA: molecular cloning, chromosomal mapping, and biological implications | journal = Science | volume = 233 | issue = 4761 | pages = 364–7 | date = July 1986 | pmid = 3014653 | doi = 10.1126/science.3014653 | bibcode = 1986Sci...233..364L }}</ref><ref name = "pmid2877664">{{cite journal | vauthors = Robakis NK, Devine-Gage EA, Jenkins EC, Kascsak RJ, Brown WT, Krawczun MS, Silverman WP | title = Localization of a human gene homologous to the PrP gene on the p arm of chromosome 20 and detection of PrP-related antigens in normal human brain | journal = Biochem. Biophys. Res. Commun. | volume = 140 | issue = 2 | pages = 758–65 | date = October 1986 | pmid = 2877664 | doi = 10.1016/0006-291X(86)90796-5 }}</ref> Expression of the [[protein]] is most predominant in the [[nervous system]] but occurs in many other tissues throughout the body.<ref name = "pmid11357156">{{cite journal | vauthors = Prusiner SB | title = Shattuck lecture--neurodegenerative diseases and prions | journal = N Engl J Med | volume = 344 | issue = 20 | pages = 1516–26 | year = 2001 | pmid = 11357156 | doi = 10.1056/NEJM200105173442006| doi-access = free }}</ref><ref name = "pmid15494743">{{cite journal | vauthors = Weissmann C | title = The state of the prion | journal = Nat Rev Microbiol | volume = 2 | issue = 11 | pages = 861–71 | year = 2004 | pmid = 15494743 | doi = 10.1038/nrmicro1025| s2cid = 20992257 }}</ref><ref name = "review2">{{cite journal | vauthors = Zomosa-Signoret V, Arnaud JD, Fontes P, Alvarez-Martinez MT, Liautard JP | title = Physiological role of the cellular prion protein | journal = Vet. Res. | volume = 39 | issue = 4 | pages = 9 | year = 2008 | pmid = 18073096 | doi = 10.1051/vetres:2007048| url = https://hal.archives-ouvertes.fr/hal-00902908/file/hal-00902908.pdf | doi-access = free }}</ref>
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== Structure ==
PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice.<ref name = "pmid21987789">{{cite journal | vauthors = Damberger FF, Christen B, Pérez DR, Hornemann S, Wüthrich K | title = Cellular prion protein conformation and function | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 42 | pages = 17308–13 | date = October 2011 | pmid = 21987789 | pmc = 3198368 | doi = 10.1073/pnas.1106325108| bibcode = 2011PNAS..10817308D | doi-access = free }}</ref> Comparison between primates is especially similar, ranging from 92.9
The primary sequence of PrP is 253 [[amino acid]]s long before [[post-translational modification]]. [[Signal peptide|Signal sequences]] in the [[amine|amino]]- and [[Carboxylic acid|carboxy]]- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and [[golden hamster]] PrP, two [[Glycosylation|glycosylated]] sites exist on helices 2 and 3 at [[Asparagine|Asn]]181 and Asn197. [[Murinae|Murine]] PrP has glycosylation sites as Asn180 and Asn196. A [[disulfide]] bond exists between [[Cysteine|Cys]]179 of the second helix and Cys214 of the third helix (human PrP<sup>C</sup> numbering).
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The precise function of PrP is not yet known. It may play a role in the transport of [[ion]]ic copper into cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of [[synapse]]s.<ref>{{cite journal | vauthors = Kanaani J, Prusiner SB, Diacovo J, Baekkeskov S, Legname G | title = Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro | journal = Journal of Neurochemistry | volume = 95 | issue = 5 | pages = 1373–86 | date = December 2005 | pmid = 16313516 | doi = 10.1111/j.1471-4159.2005.03469.x | s2cid = 24329326 | doi-access = free }}</ref> PrP<sup>C</sup> attaches to the outer surface of the [[cell membrane]] by a [[glycosylphosphatidylinositol]] anchor at its [[C-terminal]] [[serine|Ser]]231.
[[Prion protein]] contains five [[peptide|octapeptide]] repeats with sequence PHGGGWGQ (though the first repeat has the slightly
=== PrP<sup>Sc</sup> (scrapie) isoform ===
PrP<sup>Sc</sup> is a conformational isoform of PrP<sup>C</sup>, but this orientation tends to accumulate in compact, [[protease]]-resistant aggregates within neural tissue.<ref name = "pmid15272267">{{cite journal | vauthors = Ross CA, Poirier MA | title = Protein aggregation and neurodegenerative disease | journal = Nat. Med. | volume = 10 | issue = 7| pages = S10–7 | date = July 2004 | pmid = 15272267 | doi = 10.1038/nm1066| s2cid = 205383483 }}</ref> The abnormal PrP<sup>Sc</sup> isoform has a different [[secondary structure|secondary]] and [[tertiary structure]] from PrP<sup>C</sup>, but identical primary sequence. Whereas PrP<sup>C</sup> has largely alpha helical and disordered domains,<ref>{{Cite journal |last1=Riek |first1=Roland |last2=Hornemann |first2=Simone |last3=Wider |first3=Gerhard |last4=Glockshuber |first4=Rudi |last5=Wüthrich |first5=Kurt |date=1997-08-18 |title=NMR characterization of the full-length recombinant murine prion protein, m PrP(23–231) |url=https://febs.onlinelibrary.wiley.com/doi/10.1016/S0014-5793%2897%2900920-4 |journal=FEBS Letters |language=en |volume=413 |issue=2 |pages=282–288 |doi=10.1016/S0014-5793(97)00920-4 |pmid=9280298 |s2cid=39791520 |issn=0014-5793}}</ref> PrP<sup>Sc</sup> has no alpha helix and an amyloid fibril core composed of a stack of PrP molecules glued together by parallel in-register intermolecular beta sheets.
The propagation of PrP<sup>Sc</sup> is a topic of great interest, as its accumulation is a pathological cause of [[neurodegeneration]]. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrP<sup>C</sup> is caused by the presence and interaction with PrP<sup>Sc</sup>.<ref name = "pmid21350487">{{cite journal | vauthors = Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J | title = Prion propagation and toxicity in vivo occur in two distinct mechanistic phases | journal = Nature | volume = 470 | issue = 7335 | pages = 540–2 | date = February 2011 | pmid = 21350487 | doi = 10.1038/nature09768| bibcode = 2011Natur.470..540S | s2cid = 4399936 }}</ref> Strong support for this is taken from studies in which ''PRNP''-knockout mice are resistant to the introduction of PrP<sup>Sc</sup>.<ref name = "pmid8100741">{{cite journal | vauthors = Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C | title = Mice devoid of PrP are resistant to scrapie | journal = Cell | volume = 73 | issue = 7 | pages = 1339–47 | date = July 1993 | pmid = 8100741 | doi = 10.1016/0092-8674(93)90360-3| doi-access = free }}</ref> Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrP<sup>Sc</sup> and [[cytotoxicity]].<ref name = "elusive">{{cite journal | vauthors = Aguzzi A, Baumann F, Bremer J | title = The prion's elusive reason for being | journal = Annu. Rev. Neurosci. | volume = 31 | pages = 439–77 | year = 2008 | pmid = 18558863 | doi = 10.1146/annurev.neuro.31.060407.125620}}</ref>
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