User:Erin May/Sandbox 1

This structure is the form of Major Prion Protein as it appears in an non-diseased individual. This is a monomer in healthy tissues. The majority of this 3D structure is .

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

Residue 129 Val-->Met confers increased susceptibility to the catalytic unfolding of the alpha helices characteristic of spongiform encephalopathies. In monomeric form, , does not offer a possible mechanism of unfolding or aggregation. As of January 2010, only individuals with homozygous Metionine129 had been diagnosed with infectious Creutzfeldt–Jakob disease.

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.^[4]

Residue 200 Glu-->Lys. 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.^[5]

Image:Http://www.jbc.org/content/275/43/33650/F4.large.jpg ^[5]

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

The majority of this structure is beta sheets The following residues are shown on the PrP^Sc:

129 Val-->Met (susceptibility to Creutzfeldt–Jakob disease).

Residues R164 to S170 (variable region between species)^[4]

200 Glu-->Lys (present in infectious and spontaneous form of Creutzfeldt–Jakob disease)^[5]

The Cystine residues which were formerly part of disulfide bonds have been reduced catalytically without any chemical reducing agent. ^[6]

The specific residues shown alter the electrostatic properties of the surface of PrP^C, however their postions on the wild-type monomer and fully unfolded PrP^Sc, do not illustrate a clear mechanism for propagation. The dimer form clearly shows the reason for the infectious qualities of the variable and disease conforming residues.

It is theorized from this dimeric structure that the dimerization is the first step in amyloid formation and the presence of these dimers could possibly speed up the aggregation of PrP^Sc.

The following interactions and residue switching portray possible catalytic sites:

Residues 129, 200, and 164 to 170 are shown to exist right at the dimer interfaces (as noted in the previous structures). The placement of these residues within the dimer indicates the dimerization as the point of control for these specific residues.

Helix 1 (Ser 143−Tyr 157) exists at the dimer interface. ^[6]

Helix 2 (Asn 171−Thr 188) is linked to the C-terminal helix 3 (Thr 199−Tyr 225).

The switch region 189-198 is shown to be unfolded.

There are also additional intrachain van der Waals and electrostatic interactions between the switch region and helix 1 in the 3D domain-swapped dimeric crystal structure that are not possible in the monomeric NMR structure.

Hydrogen bonding between the dimers exist: Thr188 O−Gly195 N, Thr190 O−Lys194 N and Thr192 O−Thr192 N

Altered in familial: 119, 129, 226 shown

Asp 202 and Arg 220, which are located at either end of helix 3, form interchain hydrogen bonds that confer specificity to the interaction

Due to the importance of initial dimerization in the formation of prion aggregates, the step of dimerization presents a known step for treatments to target.