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1.C.48 The Prion Peptide (PrP) Family

Peptides from prion proteins such as prion protein fragment, PrP[106-126], a 21 aa peptide, forms ion channels permeable to physiological ions. Channels form in planar lipid bilayers at concentrations greater than 20μM. Heterogeneous channels of various conductances are observed for a single peptide, perhaps reflecting different oligomeric states of the channel-forming peptide in the membrane.  PrP[106-126] is protease resistant, neurotoxic, and heterogeneous. It may exist in at least two oligomeric β-sheet forms. One of its oligomeric forms is a Cu2+-sensitive fast-cation channel which may bind Cu2+ to M109 and H111 in the mouth of the channel (Kourie et al., 2003). The assembly of PrP into neurotoxic channels may underlie the toxicity associated with prion diseases. 

Four major clusters of PrPs have been identified, including shadoos, shadoo2s and prion protein-likes (cluster 1), fish prion proteins (cluster 2), tetrapode prion proteins (cluster 3) and doppels (cluster 4). The entire prion protein conformationally plastic region is conserved between eutherian prion proteins and shadoos (18-25% identity and 28-34% similarity), and there could be a potential structural compatibility between shadoos and the left-handed parallel beta-helical fold (Premzl and Gamulin 2007).

Misfolded and aggregated forms of PrP are associated with many prion diseases. A transmembrane form of PrP, favored by the pathogenic mutation, A116V, is associated with Gerstmann- Straussler-Scheinker syndrome, but no accumulation of PrP(Sc) is detected. The full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K+, and forms K+- and Ca2+-selective channels in lipid membranes. The A116V mutation greatly increases channel-formation. These channels are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels (Sabareesan et al. 2016). Upon interaction with lipid, the central hydrophobic region (109-132) probably inserts into the membrane and lines the channel. An increase in the protein-lipid stoichiometry provides a rationale for its increased channel-forming capability. Ion channel formation represents a possible mechanism of PrP-mediated neurodegeneration. 

The cellular prion protein (PrP(C)) is a ubiquitously expressed glycoprotein that is most abundant in the central nervous system. It plays a role in many cellular processes, including neuroprotection, but may also contribute to Alzheimer's disease and some cancers. It is best known for its central role in prion diseases such as Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), and scrapie (Godsave et al. 2015). These protein misfolding diseases can be sporadic, acquired, or genetic and are caused by refolding of endogenous PrP(C) into a beta sheet-rich, pathogenic form, PrP(Sc). Once prions are present in the central nervous system, they increase and spread during a long incubation period that is followed by a relatively short clinical disease phase, ending in death. PrP molecules can be broadly categorized as either 'good' (cellular) PrP(C) or 'bad' (scrapie prion-type) PrP(Sc), but both populations are heterogeneous, and different forms of PrP(C) may influence various cellular activities. Both PrP(C) and PrP(Sc) are localized predominantly at the cell surface, with the C-terminus attached to the plasma membrane via a glycosyl-phosphatidylinositol (GPI) anchor, and both can exist in cleaved forms. PrP(C) also has cytosolic and transmembrane forms, and PrP(Sc) is known to exist in a variety of conformations and aggregation states (Godsave et al. 2015).

The generalized transport reaction is:

Ions (in)  →  ions (out) 

References associated with 1.C.48 family:

Godsave, S.F., P.J. Peters, and H. Wille. (2015). Subcellular distribution of the prion protein in sickness and in health. Virus Res 207: 136-145. 25683509
Kourie, J.I. and A. Culverson. (2000). Prion peptide fragment PrP[106-126] forms distinct cation channel types. J. Neuro. Res. 62: 120-133. 11002294
Kourie, J.I. and A.A. Shorthouse. (2000). Properties of cytotoxic peptide-formed ion channels. Am. J. Physiol. Cell Physiol. 278: C1063-C1087. 10837335
Kourie, J.I., B.L. Kenna, D. Tew, M.F. Jobling, C.C. Curtain, C.L. Masters, K.J. Barnham, and R. Cappai. (2003). Copper modulation of ion channels of PrP[106-126] mutant prion peptide fragments. J. Membr. Biol. 193: 35-45. 12879164
Mani, K., F. Cheng, B. Havsmark, M. Jönsson, M. Belting, and L.A. Fransson. (2003). Prion, amyloid β-derived Cu(II) ions, or free Zn(II) ions support S-nitroso-dependent autocleavage of glypican-1 heparan sulfate. J. Biol. Chem. 278: 38956-38965. 12732622
Premzl, M. and V. Gamulin. (2007). Comparative genomic analysis of prion genes. BMC Genomics 8: 1. 17199895
Sabareesan, A.T., J. Singh, S. Roy, J.B. Udgaonkar, and M.K. Mathew. (2016). The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes. Biophys. J. 110: 1766-1776. 27119637
Taylor, D.R., I.J. Whitehouse, and N.M. Hooper. (2009). Glypican-1 mediates both prion protein lipid raft association and disease isoform formation. PLoS Pathog 5: e1000666. 19936054
Wu, D., W. Zhang, Q. Luo, K. Luo, L. Huang, W. Wang, T. Huang, R. Chen, Y. Lin, D. Pang, and G. Xiao. (2010). Copper (II) promotes the formation of soluble neurotoxic PrP oligomers in acidic environment. J. Cell. Biochem. 111: 627-633. 20564047