Human Prion Protein Dimer

Prions as a disease causing agent

Human Prion Protein in dimer form 1i4m

Caption: Holes in this sponge like brain tissue result from pockets of prion aggregation ^[1]

Prions are infectious or genetically coded misfolded proteins which act as templates upon which properly folded prion protein monomers can aggregate. Prions contain no nucleic acid such as other infectoius molecules or organisms. Human Prion Protein or Major Prion protein, exists as a normal constituent of human cells, found mostly in the brain^[2] and is called PrP^C.^[3] PrP^C is composed of mostly helix whereas the infectious form, PrP^Sc (also known as "scrapie" form), is composed of high percentage beta sheets.^[3]

The diseases prions confer are neurodegenerative disorders which result from the large scale aggregation of these proteins. This "bubbles" of protein aggregates appear clear on a pictomicrograph and resemble a sponge. Bovine Spongiform Encephalopathy(BSE), or Mad Cow Disease, is a form of Transmissible Spongiform Encephalopathy caused by ingesting bovine prions. The first known cases of BSE occurred in the 1970's and have garnered a lot of media attention. Recently, feed bans in the United States and Canada have been adopted by the government in an attempt to stop the spread of BSE between cows. This bans the use of potential materials which would contain prion proteins, whether misfolded or wild-type. ^[4] For more information about the infections related to prions see Transmissible spongiform encephalopathy at Wikipedia.

Unfolding Mechanism

Currently, the mechanism by which a template prion unfolds the helices of a properly folded prion protein is unknown. Specific residues have been shown to either confer resistance or lend themselves to this unfolding.

PrP^C natural monomer

This monomeric structure is the form of Major Prion Protein as it appears in a non-diseased individual. The majority of this 3D structure is and two small beta sheets.

The following residue alterations confer increased susceptibility to the unfolding of these alpha helices characteristic of spongiform encephalopathies.

Residue 129 Val-->Met confers increased susceptibility to contracting spongiform encephalopathies. The alteration from 129 valine to 129 methionine does not majorly change electrostatics as both are hydrophobic. The methionine group is bulkier however. Due to the limitations of viewing the monomeric form, , it does not offer a possible mechanism of unfolding or aggregation. This single residue, however has incredible actions. As of January 2010, only individuals with homozygous Metionine 129 had been diagnosed with infectious Creutzfeldt–Jakob disease.^[5]

exhibit species specific residues. This region is most variable between species. Residue shifts in this section increase or decrease susceptibility from inter-species transmission of TSE's. The more similar this region is between species, the more likely each are able to transfer infectious prions between the two.^[5]

The in the monomeric form must all be broken during the conformational change from PrP^C to PrP^Sc. ^[6]

. This residue shift changes the surface electrostatic potential in a way which alters its interactions with other prion proteins as well as chaperone proteins. The Lys residue in position 200 is found in the infectious form of Creutzfeldt–Jakob disease. Those who have Lysine in the 200 position who live long enough will develop a spontaneous form of Creutzfeldt–Jakob disease.^[7]

Caption: This shows (a&c) the electrostatic potential of wild-type Human Prion Protein with Glu200 and (b&d) the electrostatic potential of variant Lys200. ^[7]

PrP^Sc