Disease Motifs
Investigating the Biomechanics of Disease
Go back to the Home page Resources About this site Biological Research Services Contact this Site

The Human Prion Protein P04156 (PRIO_HUMAN)

The human prion protein is produced from the prion gene PRNP which is single copy gene (there is only one copy of the gene in contrast to a multiple copy gene where there are more copies) and is situated on chromosome 20. This gene is split in to three sections or exons, as they are called, with most of the prion protein being coded for largely from just one of these exons. The human prion protein is originally 253 amino acids long, this is modified with the 231 - 253 piece of the protein, being cleaved off as well as something called the 'signal peptide' (the first 22 amino acids) also being removed. So the mature form of the protein is from residues 23 to 230 and so is 208 amino acids long. Some sugars are added at residues 181 and 197 (in N-linked glycosylation), and the prion protein is linked to the cell surface by a (wait for it) glycosylphosphatidylinositol (GPI) anchor at residue 230. Don't worry about terms glycosylphosphatidylinositol and N-linked glycosylation I'll write a little bit (and only a bit) about these elsewhere.

The Amino Acid Sequence of the Human Prion Protein

These are all the 253 amino acid of the human prion protein sequence:-

Prion protein amino acid sequence

The colours represent the chemical properties of the amino acids which are usually split into four groups: acidic amino acids are red: basic amino acids are violet; non-polar neutral amino acids are green; and polar neutral amino acids are aqua.

This is the mature form of the prion protein consisting of 208 amino acids.

Truncated prion protein amino acid sequence

The Prion Protein Repeats

If you were to look at the sequence carefully you might notice that the sequence has a somewhat repetitive appearance. There seem to be a series of repeats from, residue 51 to residue 91. These are list here

This is a nonapeptide or nine amino acids from residue 51 to residue 59 and is sometimes referred to as R1. There is the P for proline at the start, followed by a Q for glutamine and there is another glutamine that ends the sequence, and these two glutamines sandwich five Gs for glycine, and one W for tryptophan.

The first octapeptide
This is the first of four octapeptides or group of eight amino acid residues and extends from residue 61 to residue 67. Notice the similarity of this and all the other octapeptides to the nonapeptide R1 shown above. One glutamine (Q) and one glycine (G) have been replaced with a histidine (H).

The second octapeptide
This is the second of the octapeptides and extends from residue 68 to residue 75.

The third octapeptide
This is the third octapeptides and extends from residue 76 to residue 83.

The fourth octapeptide
This is the fourth and last of the octapeptides extending from residue 84 to residue 91.

The HGGGW part of the octapeptide repeats have been shown to bind to copper ions and might be suggestive of some function such has copper metabolism. These octapeptide repeats occur in prion proteins found in many different species, but in avian species such as the chicken there is a different arrangement with there being a hexapeptide repeat PHNPGY instead of the octapeptide shown above.

The Prion Protein

The human prion protein can be seen then to consist of five repeats, an end bit that is cleaved off at translation, and a signal peptide which is cleaved off when the mature form of the protein is formed. I have labelled two other sections as the starter sequence and the main section, but don't get hooked up with these terms as they are meaningless really, I just made them up in order to refer to these sections should I need to.

The Full Length Human Prion Protein

Full human prion protein amino acid sequence

The Mature Human Prion Protein

Mature prion protein amino acid sequence

Location of the Normal Prion Protein

It is important to point out that the prion protein should not be considered to be solely a protein that causes diseases. The prion protein is a normal cellular protein that has some as yet unknown function in the human or animal body. The key areas where the prion protein can be found are in the neurones of the central nervous system (CNS) but can also be found in other places such as: blood lymphocytes; gastro-epithelial cells; heart, kidney and muscle tissues. The key areas of the brain where the prion protein is found in abundance is in the hippocampus, and important centre associated with memory, and this agrees with the fact that one of the first symptoms of prion disease is memory loss.

Normal Cellular and Abnormal Disease, Prion Proteins

Now both the normal cellular prion protein and the abnormal disease have the same sequence of amino acids however there is a difference in conformation or shape of the prion protein that leads to prion disease. So all that happens is the normal cellular protein for some unknown reason adopts a different shape. And as you may know the shape of a protein can determine its function. It is this altered structure that some people believe causes disease. The normal cellular prion protein can sometimes be annotated as PrPC were the 'C' stands for cellular protein. Whereas the disease form of the protein can be designated as PrPSc, with the 'Sc' standing for scrapie.

The normal cellular protein has three α-helices (spring-like structures) and two short anti-parallel β-sheets (straight strand-like structures). In the disease prion protein there is a marked reduction in the amount of the protein structure that forms α-helices and an increase in the proportion of the protein adopting a β-sheet shape. This increase in a β-sheet formation seems to make the protein more resistant to degradation. Proteases are proteins that can break apart or dissolve other proteins. The normal cellular prion protein will be totally dissolved by proteases but the disease prion protein will be dissolved up to a point leaving a fragment of roughly around 142 amino acids, sometimes referred to as the PrP 27-30 fragment (it has a molecular mass of 27-30 kilo-Daltons if that means anything to you). This remaining fragment from the disease prion protein has a 43 percent of its structure taking up a β-sheets structure and no α-helices. This fragment starts around the position just after the last of the four octapeptide repeats and continues to residue 230.

Causes of the Change of Conformation

It is believed that some small amount of abnormal protein if ingested or inoculated in to a healthy person will induce normal healthy prion protein to take up the disease structure, perhaps by acting like some template, and hence causing disease. A disease that is transmissible. This does not really answer the question of how the abnormal protein is formed in the first place as something as to be responsible for generating the first abnormal protein. It has been suggested that the first abnormal protein may have been generated by a random spontaneous change of conformation. There are others who think that the whole disease is generated by some microbial agent, perhaps virus, although no microbial agents have yet been clearly shown to be responsible.


If the change in shape of the prion protein is a spontaneous event without any reason then perhaps there is not too much one can do to study this event, as it is something that has just happened and we have to just avoid being contaminated with deviant and deadly conformations of the protein. Burn all your infected livestock and bring in another more resilient breed. Fine for farm animals but not so good for the human population should there be a variant CJD outbreak in the UK. On the other hand, there are some individuals who develop prion disease for no known reason and presumably have not eaten or been infected with abnormal prion protein as far as it can be known. They have developed a prion disease in a sporadic manner so to speak, and there are others who seem to have genetic susceptibility to developing a prion disease. It is these last groups that are of interest as they can provide the key to the origin and causes of some of the prion diseases. It is part of the goal of this work to look at the sequence of the prion protein and try and find some indication of the function of the prion protein by searching for active sites and also the connection to any microbial and/or immunogenic agent via a so called 'disease' motif.

Some links to prion protein analysis

PRIO_HUMAN protein sequence analysis

PRIO_HUMAN polymorphic sequence analysis