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 mammalian prion protein (PrP) engages with the ribosome-Sec61 translocation channel complex to generate different topological variants that are either physiological, or involved in neurodegenerative diseases. Kriegler et al. 2020 described cotranslational folding and translocation mechanisms of PrP coupled to an Xbp1-based arrest peptide (AP) as folding sensor, to measure forces acting on PrP nascent chain. Our data reveal two main pulling events followed by a minor third one exerted on the nascent chains during their translocation. A specific sequence within an intrinsically disordered region, containing a polybasic and glycine-proline rich residues, modulates the second pulling event by interacting with the TRAP complex. The authors also delineate the sequence of events involved in generating PrP toxic transmembrane topologies during its synthesis revealing how the folding of such a topological complex protein occurs, where marginal pulling by the signal sequence, together with the flanking downstream sequence in the mature domain, primarily drives an overall inefficient translocation causing the nascent chain to adopt alternative topologies (Kriegler et al. 2020).
The generalized transport reaction is:
Ions (in) → ions (out)
Major prion protein, PrP or PRNP, of 253 aas and 3 possible TMSs, N-terminal, middle, and C-terminal. Its primary physiological function is
unclear. It has cytoprotective activity against internal or environmental
stresses and may play a role in neuronal development and synaptic
plasticity. May be required for neuronal myelin sheath maintenance, but may
play a role in iron uptake and iron homeostasis. Soluble oligomers are
toxic to cultured neuroblastoma cells and induce apoptosis (Mani et al. 2003; Taylor et al. 2009; Wu et al. 2010). The mouse orthologue (P04925), particularly the A116V mutant, forms ion channels in lipid membranes (Sabareesan et al. 2016). It's cell biology has been reviewed (Sarnataro et al. 2017).
PrP of Homo sapiens
Prion protein of 497 aas and 3 TMSs
Prion protein of Paralichthys olivaceus (Bastard halibut) (Hippoglossus olivaceus)
Prion-like protein, Doppel (PRND) of 176 aas and 2 TMSs
Doppel of Homo sapiens
Shadow of prion protein, SPRN or SHO, of 151 aas and 3 TMSs
SPRN of Homo sapiens