My understanding is:

The PrP gene in human cells is expressed as both PrP-c (normal protein) and PrP-sc (prion disease protein). This happens post transcriptionally, that is, the normal and the diseased protein are not distinguished based on genetic mutations, rather they are synthesized based on the same gene, but differ in their tertiary structures, which makes their functions also different.

If the amino acid sequence of both proteins is the same (same gene), then what determines whether the synthesized protein will take the disease-causing tertiary structure or the normal one? Is it due to post-translational modifications?

And finally (I apologize for advance for multiple questions): how do prions, which are void of nucleic acids (being proteins), integrate into the genome of a newly infected host by reverse translation, and become a familial disease?

up vote 2 down vote accepted

If the amino acid sequence of both proteins is the same, what determines whether the synthesized protein will take the disease-causing tertiary structure or the normal one?

PrP-C and PrP-Sc do indeed have the same primary structure. However, they differ in secondary and tertiary structure. The protein can take more than one shape (conformation), where the likely conformation spaces taken by the protein are due to chemical and physical interactions. Many proteins can change their shape, often this is not well understood in detail. However, we know that the conformational space of some proteins allows for several, stable conformations of a single protein; the factors which stabilize it in a conformation or cause it to switch are difficult to understand in vivo.

PrP-Sc tends to accumulate in compact, protease-resistant aggregates. Circular dichroism shows that normal PrPC had 43% alpha helical and 3% beta sheet content, whereas PrPSc was only 30% alpha helix and 43% beta sheet. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet structure in place of the normal α-helix structure. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow.

Prion proteins therefore propagate accumulation of more and more prion proteins.

Is it due to post-translational modifications?

No.

How do prions, which are void of nucleic acids, integrate into the genome of a newly infected host by reverse translation, and become a familial disease?

They do not enter the genome through reverse translation. The DNA sequence itself is mutated and the mutation drifts across generations for as long as it is being passed on through the germline.

  • In the first paragraph of your response, you said that “PrP-C and PrP-Sc do indeed have the same primary structure”, so how is it that you later say “the DNA sequence itself is mutated”? If they both result from the same gene, then shouldn’t something other than the “DNA sequence itself” be causing infection persistence through the gene line? – P. SN Aug 10 at 11:00
  • This paper here suggests that PrP-sc is physically passed on through cytoplasmic division of cells into daughter cells, so that the phenotype rather than the genotype is passed on, and if the phenotype is advantageous for survival, a mutation might incorporate it into the genome. omicsonline.org/open-access/… – P. SN Aug 10 at 11:07
  • The protein is the infectious agent. The protein spreads through to new cells, causing the refolding of PrP-C. This does not occur in a DNA-dependent fashion. You are misusing the words phenotype and genotype, they do not refer to a protein/DNA dichotomy. Different protein isoforms can be made with a single gene. Mutations are not incorporated into genomes, they occur WITHIN genomes. Genomes are, colloquially speaking, records of mutations. Prion disease is a protein environment disease, it is not innately that prion proteins cause the disease (hence PrP-C, the healthy variant). – S Pr Aug 10 at 11:12

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