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General intro
Prion proteins are a common part of cell surface proteins in the mammalian nervous system, and they can, upon change of its conformation, become a highly infectious and pathogenic agent. The physiological form (PrPC) is encoded by the PRNP gene on chromosome 20 and when misfolded and aggregated, the pathological form (PrPSc) occurs, lacking any specific nucleic acid and its primary structure being determined by the PrPC form. When accumulated in the central nervous system (CNS) of mammals, PrPSc is known to be responsible for uprise of several untreatable progressive neurodegenerative diseases, generally called as transmissible spongiform encephalopathies (TSEs). These include kuru, fatal familial insomnia (FFI) and Creutzfeld-Jacob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, transmissible mink encephalopathy (TME) in mink, feline spongiform encephalopathy (FSE) in cat or chronic wasting disease (CWD) in deer and elk [1].
Protein structure
The PrPSc differs from PrPC solely in conformation and is its isoform. The mature PrPC consists of approx. 208 amino acids, arranged as a disordered N-terminus and a globular C-terminal domain consisting of three α-helices and a short, antiparallel β-pleated sheet [2][3]. There is a GPI membrane anchor at the C-terminus that tethers the protein to cell membranes and proteins that are secreted and lacking the anchor component has been proven to be unaffected by the infectious isoform [4]. In contrast to the natural form of prion protein with only about 3 % of β-sheet secondary structure, the PrPSc form has about 47 % of the secondary structure in β-sheets [5] that create a core of four-rung β-solenoid fold [6]. Accordingly, they also differ in their properties. PrPC is soluble, has a life-span between 2 and 4 hours, and is sensitive to proteolytic cleavage – when exposed to proteases, the protein is degraded completely [5]. The two most important cleavage events are the α cleavage which removes the unstructured N-terminal tail and leaves the globular domain attached to the cell membrane, and the cleavage on the C-terminal end (termed PrPC shedding) which releases PrPC into the extracellular space [7]. Under the same conditions, PrPSc is hydrolysed by proteases only partially by forming resistant core fragment PrP 27-30 [5]. In addition, it is insoluble in detergents and has a very long half-life, therefore accumulates in tissues easily. It has a tendency to form aggregates and fibrillar structures and is generally susceptible to oligomerization, whereas the PrPC form mainly exist as a monomer [8]. Monomeric PrPSc has never been isolated.
References
- ↑ Imran M, Mahmood S. An overview of animal prion diseases. Virol J. 2011 Nov 1;8:493. doi: 10.1186/1743-422X-8-493. PMID:22044871 doi:http://dx.doi.org/10.1186/1743-422X-8-493
- ↑ Zahn R, Liu A, Luhrs T, Riek R, von Schroetter C, Lopez Garcia F, Billeter M, Calzolai L, Wider G, Wuthrich K. NMR solution structure of the human prion protein. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):145-50. PMID:10618385
- ↑ Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K. NMR structure of the mouse prion protein domain PrP(121-321). Nature. 1996 Jul 11;382(6587):180-2. PMID:8700211 doi:10.1038/382180a0
- ↑ Chesebro B, Trifilo M, Race R, Meade-White K, Teng C, LaCasse R, Raymond L, Favara C, Baron G, Priola S, Caughey B, Masliah E, Oldstone M. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science. 2005 Jun 3;308(5727):1435-9. doi: 10.1126/science.1110837. PMID:15933194 doi:http://dx.doi.org/10.1126/science.1110837
- ↑ 5.0 5.1 5.2 Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, et al.. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962-6. PMID:7902575
- ↑ Wille H, Requena JR. The Structure of PrP(Sc) Prions. Pathogens. 2018 Feb 7;7(1). pii: pathogens7010020. doi: 10.3390/pathogens7010020. PMID:29414853 doi:http://dx.doi.org/10.3390/pathogens7010020
- ↑ Wille H, Requena JR. The Structure of PrP(Sc) Prions. Pathogens. 2018 Feb 7;7(1). pii: pathogens7010020. doi: 10.3390/pathogens7010020. PMID:29414853 doi:http://dx.doi.org/10.3390/pathogens7010020
- ↑ Cohen FE, Prusiner SB. Pathologic conformations of prion proteins. Annu Rev Biochem. 1998;67:793-819. doi: 10.1146/annurev.biochem.67.1.793. PMID:9759504 doi:http://dx.doi.org/10.1146/annurev.biochem.67.1.793
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