Major prion protein precursor
Homo sapiens (human)
Creutzfeldt-Jacob disease (CJD) and related diseases were first described in the 1920's, named after the two German neurologists, Creutzfeldt and Jacob, who studied this disease. It was much later shown that the disease is related to the sheep disease scrapie, which had been known since the 18th century. It is a neurological disease, affecting the brain, which is characterized by the inability of the patient to control his movement, by paralysis, increasing loss of cognitive capacity (dementia) and in the end death. Studies of cannibalistic tribes in New Guinea showed a similar disease, kuru, and it was observed that the disease can be transmitted by digestion. In general, viruses, typical infectious agents, are damaged by UV-radiation due to defects introduced into the DNA by radiation. It was observed that scrapie was UV-resistant and thus suspected that the infectious agents might be unrelated to any nucleic acid containing compounds. Prusiner's work on prion protein (PrP) then showed that this protein must be the likely causative agent.
The prion protein PrP can exist in two forms. One is the normal, cellular structure known as PrPc and the other is the disease-related form known as PrPsc or scrapie prion protein. PrPc is a normal protein with a high content of alpha-helices and can readily be digested by proteases. The structure shown here is also a PrPc form, has three alpha-helices and a short anti-parallel beta-sheet.
PrPsc on the other hand has a high content of beta-sheet structure. It is in- soluble in detergents and resistant to digestion by proteases. Other than by their difference in structure they seem to be identical chemically. PrPc, found attached to neurons, is assumed to associated with brain activity. PrPsc forms aggregates which accumulate in the brain as plaques. These aggregates progressively diminish brain function and the final stage of the disease is death. Such an observation in itself is not remarkable. As an example, there is a point-mutation in hemoglobin, leading to aggregation and sickle-cell disease. This disease is inherited and it either exists or does not exist. What is remarkable in the case of prion protein is the fact, that PrPsc seems to be infectious, that it can convert otherwise healthy PrPc protein into the disease-related PrPsc protein. Diseases caused by defective prion protein are related to the protein's structure. The fact that bovine and human prion protein have similar overall structures, lends credence to the assumption that the digestion of meat from cows infected with BSE may result in human CJD.
Protein Data Bank (PDB)
author: Arno Paehler