Summary

Prion/Doppel alpha-helical domain

The prion protein is thought to be the infectious agent that causes transmissible spongiform encephalopathies, such as scrapie and BSE. It is thought that the prion protein can exist in two different forms: one is the normal cellular protein, and the other is the infectious form which can change the normal prion protein into the infectious form. It has been found that the prion alpha-helical domain is also found in the Doppel protein.

Literature references

Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K; , Nature 1996;382:180-182.: NMR structure of the mouse prion protein domain PrP(121-321). PUBMED:8700211
Riek R, Hornemann S, Wider G, Glockshuber R, Wuthrich K; , FEBS Lett 1997;413:282-288.: NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231). PUBMED:9280298

InterPro entry IPR000817

Prion protein (PrP-c) PUBMED:2572197, PUBMED:1916104, PUBMED:2908696 is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal and infected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) PUBMED:12354606.

The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process.

In humans, PrP is a 253 amino acid protein, which has a molecular weight of 35-36 kDa. It has two hexapeptides and repeated octapeptides at the N-terminus, a disulphide bond and is associated at the C-terminus with a GPI, which enables it to anchor to the external part of the cell membrane. The secondary structure of PrP-c is mainly composed of alpha-helices, whereas PrP-sc is mainly beta-sheets: transconformation of alpha-helices into beta-sheets has been proposed as the structural basis by which PrP acquires pathogenicity in TSEs. The three-dimensional structures shows the protein to be made of a globular domain which includes three alpha-helices and two small antiparallel beta-sheet structures, and a long flexible tail whose conformation depends on the biophysical parameters of the environment. Crystals of the globular domain of PrP have recently been obtained; their analysis suggests a possible dimerisation of the protein through the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulphide bond.

Gene Ontology

Cellular component	membrane (GO:0016020)
Biological process	protein homooligomerization (GO:0051260)

External database links

PANDIT:	PF00377
PRINTS:	PR00341
PROSITE:	PDOC00263
SCOP:	2prp
SYSTERS:	Prion
Transporter classification:	1.C.48

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (7) Full (589) NCBI (2652) Metagenomics (4)
Viewer:

Formatting options

Alignment:	Seed (7) Full (589)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (7) Full (589) NCBI (2652) Metagenomics (4)
Full length sequences	Full-sequences (589)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Prosite

Previous IDs:

prion;

Type:

Domain

Author:

Bateman A, Finn RD

Number in seed:

7

Number in full:

589

Average length of the domain:

111.20 aa

Average identity of full alignment:

72 %

Average coverage of the sequence by the domain:

49.18 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	25.0	25.0
Trusted cut-off	36.9	36.7
Noise cut-off	17.8	15.8

Model length:

117

Family (HMM) version:

11

Download:

download the raw HMM for this family

Species distribution

Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the MSD group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Prion domain has been found.

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Family: Prion (PF00377)

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