We now know a good deal more about Creutzfeldt and Jakob Disease (CJD) and the category of diseases it is a part of, Transmissible Spongiform Encephalopathy (TSE) diseases, by way of the recent work done on the Prion Protein (PrP) itself. PrP is naturally a single-gene, simple protein that is expressed fairly ubiquitously in mammals with an increased prevalence in the Central Nervous System (CNS) (Collinge, 1994). PrP is an about 204 residues (after post-translational modification) long, extracellularly membrane anchored protein expressed throughout the body and encoded by the gene PRPNP located on chromosome 20. While several functions for PrP have been proposed throughout the body, there is still no definitive understanding for its functionality.
The interesting aspect about CJD, and other TSE diseases, is that the difference between the naturally occurring and perfectly harmless prion protein and the virulent prion that brings about rapid, grotesque, and unpreventable death is only a change in conformation (Ma, 2002). As a genetic disease, we would expect there to be some sort of genetic mutation or coding error when transcribing or translating the gene product, which would lead to some primary sequence mutation on the protein that ultimately effects that individually miss coded protein ability to function. However, there is no primary sequence difference between the two forms of the prion protein (Ma, 2002). The prion protein’s two different organizations of secondary structures are designated PrP cellular (C) and PrP scrapie (Sc) (Kupfer, 2009).
Current research has yet to fully describe all of the functions that PrP(C) performs in the body but there are several proposed functions for the protein depending on the tissue it is expressed in. As PrP is known to be expressed in most cells in relatively low concentrations throughout the body and seen to be upregulated in response to some infectious agents, PrP(C) is currently speculated to play some role in the innate immune system, although there is still not a large body of research around the function of PrP(C) in the periphery (Kupfer, 2009). Contemporary research is more focused around the role PrP(C) plays in neuroplasticity at the synapse, primarily in the CNS but also PNS (Mani, 2003).
PrP(C) is found anchored to the extracellular side of the membrane via a glycosylphosphatidylinositol (GPI) anchor molecule attached at its C-terminus. One specific function that the PrP(C) is proposed to perform is to bind and transport Cu2+ ions to the core protein of glypican-1 (GPC1), a heparan sulfate-substituted proteoglycan also anchored to the extracellular side of the membrane, to facilitate the binding of nitric oxide to a cystine residue in GPC1 making it “S-nitrosylated” and reducing the Cu2+ to Cu1+ in the reaction (Mani, 2003). The S-nitrosylated GPC1 then interacts with several important growth factors for the CNS to control brain development and overall functioning losing its nitric oxide in the process. PrP(C) has been shown to have a high affinity for metal ions like Cu2+, Zn2+, and Fe3+ with a metal binding domain of about 12 highly conserved residues between positions 61 and 87 on the protein (Mani, 2003). A knockout study of prion protein gene in mice showed minor brain development stunting which would be expected if this proposed mechanism was correct and a removal of PrP(C) would lead to a down regulation of GPC1 (Mani, 2003).
While the structure for the complete PrP has yet to be “solved” in either form, there is still a large body of research that allows for the approximation of the secondary structure. CyoEM and X-ray crystallography studies have primary separated the approximately 200 residue long, mature, PrP(C) prion protein into a N-domain spanning residues 23-~124 (after the N-terminus signaling domain is removed post-translationally) and a C-domain with residues~125-~231 (Zahn, 2000). Current imaging techniques have been unable to properly capture the more variable N-domain and have only been able to find the structure for the more conserved, globular C-domain. It is also the case that individual PrP(Sc) prion proteins have yet to be purified and visual “solved” with these types of techniques.
Other than the afore mentioned metal binding site on the N-domain of the PrP(C) structure there is also some conserved alpha helical structure but is otherwise considered fairly variable and not properly imaged with any particular motifs (Zahn, 2000). The secondary structure of the C-domain is far more understood with a loose, single pair antiparallel beta sheet formed between residues 128-131 and 161-164 along with three alpha helixes formed from residues 144-154, 173-194, and 200-228 (Zahn, 2000). The following image is a color-coded snapshot for the ribbon diagram of the PrP(C) C-domain from a paper by Zahn et al. (PDB: 1QLX)
In the image the sites of mutation associated with familial CJD are marked in orange, a Cys-Cys bond (179,214) is in red, and the two sites of glycosylation (181,197) in blue, exact attached carbohydrate not specified. Not pictured is the GPI anchored S230 C-terminus that holds the protein to the membrane as mentioned above (Zahn, 2000).
While research is still developing on the actual function of PrP, the main reason that TSE diseases are as well-known as they are now is because of its ability to transmit between different species as what the issue with “Mad Cow” or vCJD. This, as much as anything, proves that the prion protein, the transmission agent, must be fairly highly conserved at least amongst mammals which makes it seem like whatever functions that this protein is performing must be at least somewhat evolutionarily selected for, meaning that PrP(C) must still provide some sort of decently important role in the body.
Collinge, J., M. A. Whittington, K. C. Sidle, C. J. Smith, M. S. Palmer, A. R. Clarke, and J. G. Jefferys. “Prion Protein Is Necessary for Normal Synaptic Function.” Nature 370, no. 6487 (July 28, 1994): 295–97. https://doi.org/10.1038/370295a0.
Kupfer, L, W Hinrichs, and M.H Groschup. “Prion Protein Misfolding.” Current Molecular Medicine 9, no. 7 (September 2009): 826–35. https://doi.org/10.2174/156652409789105543.
Ma, Jiyan, and Susan Lindquist. “Conversion of PrP to a Self-Perpetuating PrPSc-like Conformation in the Cytosol.” Science 298, no. 5599 (November 29, 2002): 1785–88. https://doi.org/10.1126/science.1073619.
Mani, Katrin, Fang Cheng, Birgitta Havsmark, Mats Jönsson, Mattias Belting, and Lars-Åke Fransson. “Prion, Amyloid β-Derived Cu(II) Ions, or Free Zn(II) Ions Support S-Nitroso-Dependent Autocleavage of Glypican-1 Heparan Sulfate.” Journal of Biological Chemistry 278, no. 40 (October 3, 2003): 38956–65. https://doi.org/10.1074/jbc.M300394200.
Zahn, Ralph, Aizhuo Liu, Thorsten Lührs, Roland Riek, Christine von Schroetter, Francisco López García, Martin Billeter, Luigi Calzolai, Gerhard Wider, and Kurt Wüthrich. “NMR Solution Structure of the Human Prion Protein.” Proceedings of the National Academy of Sciences 97, no. 1 (January 4, 2000): 145–50. https://doi.org/10.1073/pnas.97.1.145.