Major prion protein

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(Redirected from
PRNP
)
Not to be confused with prions, infectious forms of proteins which have so far been observed in almost all instances to be forms of PRNP, but need not be.
PRNP
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000171867

ENSMUSG00000079037

UniProt

P04156

P04925

RefSeq (mRNA)

NM_001278256
NM_011170

RefSeq (protein)

NP_001265185
NP_035300

Location (UCSC)Chr 20: 4.69 – 4.7 MbChr 2: 131.75 – 131.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Major prion protein (PrP) is encoded in the human body by the PRNP gene also known as CD230 (cluster of differentiation 230).[5][6][7][8] Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the body.[9][10][11]

The protein can exist in multiple

fatal familial insomnia (FFI), Gerstmann–Sträussler–Scheinker syndrome (GSS), kuru, and variant Creutzfeldt–Jakob disease
(vCJD). Similarities exist between kuru, thought to be due to human ingestion of diseased individuals, and vCJD, thought to be due to human ingestion of BSE-tainted cattle products.

Gene

Chromosome 20

The human PRNP gene is located on the short (p) arm of

chromosome 20 between the end (terminus) of the arm and position 13, from base pair
4,615,068 to base pair 4,630,233.

Structure

PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice.

glycophosphatidylinositol (GPI) membrane anchor at the COOH-terminal tethers PrP to cell membranes, and this proves to be integral to the transmission of conformational change; secreted PrP lacking the anchor component is unaffected by the infectious isoform.[14]

The primary sequence of PrP is 253 amino acids long before post-translational modification. Signal sequences in the amino- and carboxy- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and golden hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond exists between Cys179 of the second helix and Cys214 of the third helix (human PrPC numbering).

PrP messenger RNA contains a pseudoknot structure (prion pseudoknot), which is thought to be involved in regulation of PrP protein translation.[15]

Ligand-binding

The mechanism for conformational conversion to the scrapie isoform is speculated to be an elusive ligand-protein, but, so far, no such compound has been identified. However, a large body of research has developed on candidates and their interaction with the PrPC.[16]

heavy metal toxicity.[17][18]

PrPC (normal cellular) isoform

Although the precise function of PrP is not yet known, it is possibly involved in the transport of

C-terminal Ser
231.

Prion protein contains five octapeptide repeats with sequence PHGGGWGQ (though the first repeat has the slightly-modified, histidine-deficient sequence PQGGGGWGQ). This is thought to generate a copper-binding domain via nitrogen atoms in the histidine imidazole side-chains and deprotonated amide nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, pH-dependent. NMR shows copper binding results in a conformational change at the N-terminus
.

PrPSc (scrapie) isoform

PrPSc is a conformational isoform of PrPC, but this orientation tends to accumulate in compact,

tertiary structure from PrPC, but identical primary sequence. Whereas PrPC has largely alpha helical and disordered domains,[21] PrPSc has no alpha helix and an amyloid fibril core composed of a stack of PrP molecules glued together by parallel in-register intermolecular beta sheets. [22][23][24] This refolding renders the PrPSc isoform extremely resistant to proteolysis
.

The propagation of PrPSc is a topic of great interest, as its accumulation is a pathological cause of

neurodegeneration. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSc.[25] Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSc.[26] Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSc and cytotoxicity.[27]

Polymorphisms at sites 136, 154, and 171 are associated with varying susceptibility to ovine scrapie. (These ovine sites correspond to human sites 133, 151, and 168.) Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whereas PrP-ARR is associated with resistance. The National Scrapie Plan of the UK aims to breed out these scrapie polymorphisms by increasing the frequency of the resistant allele.[28] However, PrP-ARR polymorphisms are susceptible to atypical scrapie, so this may prove unfruitful.

Function

Nervous system

The strong association to neurodegenerative diseases raises many questions of the function of PrP in the brain. A common approach is using PrP-knockout and

transgenic mice to investigate deficiencies and differences.[29] Initial attempts produced two strains of PrP-null mice that show no physiological or developmental differences when subjected to an array of tests. However, more recent strains have shown significant cognitive abnormalities.[16]

As the null mice age, a marked loss of

Purkinje cells in the cerebellum results in decreased motor coordination. However, this effect is not a direct result of PrP's absence, and rather arises from increased Doppel gene expression.[30] Other observed differences include reduced stress response and increased exploration of novel environments.[31][32]

Fatal familial insomnia is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP's involvement in sleep-wake cycles.[33] In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.[34]

Memory

While null mice exhibit normal learning ability and

kinases PKA and ERK1/2.[37][38]

Further support for PrP's role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV.[39] Down syndrome patients with a single valine substitution have been linked to earlier cognitive decline.[40] Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline.[41][42][43] All of these studies investigated differences in codon 129, indicating its importance in the overall functionality of PrP, in particular with regard to memory.

Neurons and synapses

PrP is present in both the pre- and post-synaptic compartments, with the greatest concentration in the pre-synaptic portion.

synaptic cleft. In this role, the protein could serve as either a copper homeostasis mechanism, a calcium modulator, or a sensor for copper or oxidative stress.[45] Loss of PrP function has been linked to long-term potentiation (LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the hippocampus.[46][47]

Some research indicates PrP involvement in neuronal development, differentiation, and neurite outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth with a series of kinases.[27][48]

Immune system

Though most attention is focused on PrP's presence in the nervous system, it is also abundant in immune system tissue. PrP immune cells include hematopoietic stem cells, mature lymphoid and myeloid compartments, and certain

monocytes. T cell activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immunoresponse to transmissible spongiform encephalopathies (TSE), neurodegenerative diseases caused by prions, could stem from the tolerance for PrPSc.[49]

Muscles, liver, and pituitary

PrP-null mice provide clues to a role in muscular physiology when subjected to a forced swimming test, which showed reduced locomotor activity. Aging mice with an overexpression of PRNP showed significant degradation of muscle tissue.

Though present, very low levels of PrP exist in the liver and could be associated with liver fibrosis. Presence in the pituitary has been shown to affect neuroendocrine function in amphibians, but little is known concerning mammalian pituitary PrP.[16]

Cellular

Varying expression of PrP through the cell cycle has led to speculation on involvement in development. A wide range of studies has been conducted investigating the role in cell proliferation, differentiation, death, and survival.[16] Engagement of PrP has been linked to activation of signal transduction.

Modulation of signal transduction pathways has been demonstrated in cross-linking with antibodies and ligand-binding (hop/STI1 or copper).

GPI raft in the lipid bilayer supports claims of an extracellular scaffolding function.[16]

Diseases caused by PrP misfolding

Main article: Transmissible spongiform encephalopathy

More than 20 mutations in the PRNP gene have been identified in people with inherited

prion diseases, which include the following:[50][51]

The conversion of PrPC to PrPSc conformation is the mechanism of transmission of fatal, neurodegenerative transmissible spongiform encephalopathies (TSE). This can arise from genetic factors, infection from external source, or spontaneously for reasons unknown. Accumulation of PrPSc corresponds with progression of neurodegeneration and is the proposed cause. Some PRNP mutations lead to a change in single amino acids (the building-blocks of proteins) in the prion protein. Others insert additional amino acids into the protein or cause an abnormally short protein to be made. These mutations cause the cell to make prion proteins with an abnormal structure. The abnormal protein PrPSc accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases.

Several other changes in the PRNP gene (called polymorphisms) do not cause prion diseases but may affect a person's risk of developing these diseases or alter the course of the disorders. An allele that codes for a PRNP variant, G127V, provides resistance to kuru.[54]

In addition, some prion diseases can be transmitted from external sources of PrPSc.[55]

  • Scrapie – fatal neurodegenerative disease in sheep, not transmissible to humans
  • Bovine spongiform encephalopathy (mad-cow disease) – fatal neurodegenerative disease in cows, which can be transmitted to humans by ingestion of brain, spinal, or digestive tract tissue of an infected cow
  • Kuru – TSE in humans, transmitted via funerary cannibalism. Generally, affected family members were given, by tradition, parts of the central nervous system according to ritual when consuming deceased family members.

Alzheimer's disease

PrPC protein is one of several cellular receptors of soluble

transgenic models of Alzheimer's, attenuated the epilepsy-induced death phenotype seen in a subset of these animals.[56] Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer's.[56][57][58]

In humans, the

PSEN1 and APOE, to compound risk for both Alzheimer's and sporadic Creutzfeldt–Jakob disease.[56] A point mutation on codon 102 of PRNP at least in part contributed to three separate patients' atypical frontotemporal dementia within the same family, suggesting a new phenotype for Gerstmann–Sträussler–Scheinker syndrome.[56][60] The same study proposed sequencing PRNP in cases of ambiguously diagnosed dementia, as the various forms of dementia can prove challenging to differentially diagnose.[60]

Research

In 2006 the production of cattle lacking PrPC form of the major prion protein (PrP) protein was reported which were resistant to prion propagation with no apparent developmental abnormalities. Besides the study of bovine products free of prion proteins another use could be so that human pharmaceuticals can be made in their blood without the danger that those products might get contaminated with the infectious agent that causes mad cow.[61][62]

Interactions

A strong

Hsp90 organizing protein; also called STI1 (Stress-induced protein 1)).[63][64]

References

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External links
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