Function: May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu2+ or ZN2+ for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains
By similarity. Ref.15 Ref.20 Ref.23
Subunit structure: Monomer and homodimer. Has a tendency to aggregate into amyloid fibrils containing a cross-beta spine, formed by a steric zipper of superposed beta-strands. Soluble oligomers may represent an intermediate stage on the path to fibril formation. Copper binding may promote oligomerization. Interacts with GRB2, APP, ERI3/PRNPIP and SYN1. Mislocalized cytosolically exposed PrP interacts with MGRN1; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement
By similarity. Interacts with KIAA1191. Ref.22 Ref.23 Ref.24 Ref.28 Ref.29 Ref.30 Ref.33 Ref.34 Ref.35
Subcellular location: Cell membrane; Lipid-anchor ? GPI-anchor. Golgi apparatus. Note: Targeted to lipid rafts via association with the heparan sulfate chains of GPC1. Colocates, in the presence of CU2+, to vesicles in para- and perinuclear regions, where both proteins undergo internalization. Heparin displaces PRNP from lipid rafts and promotes endocytosis. Ref.18 Ref.20Isoform 2: Cytoplasm. Nucleus. Note: Accumulates outside the secretory route in the cytoplasm, from where it relocates to the nucleus. Ref.18 Ref.20
Domain: The normal, monomeric form, PRPN(C), has a mainly alpha-helical structure. Misfolding of this form produces a disease-associated, protease-resistant form, PRPN (Sc), accompanied by a large increase of the beta-sheet content and formation of amyloid fibrils. These fibrils consist of a cross-beta spine, formed by a steric zipper of superposed beta-strands. Disease mutations may favor intermolecular contacts via short beta strands, and may thereby trigger oligomerization. In addition, the heparan-sulfate proteoglycan, GPC1, promotes the association of PRPN (C) to lipid rafts and appears to facilitate the conversion to PRPN (Sc). Ref.22 Ref.23 Ref.28 Ref.29 Ref.33 Ref.35Contains an N-terminal region composed of octamer repeats. At low copper concentrations, the sidechains of His residues from three or four repeats contribute to the binding of a single copper ion. Alternatively, a copper ion can be bound by interaction with the sidechain and backbone amide nitrogen of a single His residue. The observed copper binding stoichiometry suggests that two repeat regions cooperate to stabilize the binding of a single copper ion. At higher copper concentrations, each octamer can bind one copper ion by interactions with the His sidechain and Gly backbone atoms. A mixture of binding types may occur, especially in the case of octamer repeat expansion. Copper binding may stabilize the conformation of this region and may promote oligomerization. Ref.22 Ref.23 Ref.28 Ref.29 Ref.33 Ref.35
Post-translational modification: The glycosylation pattern (the amount of mono-, di- and non-glycosylated forms or glycoforms) seems to differ in normal and CJD prion.Isoform 2 is sumoylated with SUMO1
By similarity.
Polymorphism: The five tandem octapeptide repeats region is highly unstable. Insertions or deletions of octapeptide repeat units are associated to prion disease.
Involvement in disease: PrP is found in high quantity in the brain of humans and animals infected with neurodegenerative diseases known as transmissible spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler disease (GSD), Huntington disease-like type 1 (HDL1) and kuru in humans; scrapie in sheep and goat; bovine spongiform encephalopathy (BSE) in cattle; transmissible mink encephalopathy (TME); chronic wasting disease (CWD) of mule deer and elk; feline spongiform encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) in nyala and greater kudu. The prion diseases illustrate three manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to occur after consumption of prion-infected foodstuffs. Ref.20 Ref.39 Ref.40 Ref.42 Ref.43 Ref.46 Ref.47 Ref.50 Ref.51 Ref.55Creutzfeldt-Jakob disease (CJD) [MIM:123400]: Occurs primarily as a sporadic disorder (1 per million), while 10-15% are familial. Accidental transmission of CJD to humans appears to be iatrogenic (contaminated human growth hormone (HGH), corneal transplantation, electroencephalographic electrode implantation, etc.). Epidemiologic studies have failed to implicate the ingestion of infected animal meat in the pathogenesis of CJD in human. The triad of microscopic features that characterize the prion diseases consists of (1) spongiform degeneration of neurons, (2) severe astrocytic gliosis that often appears to be out of proportion to the degree of nerve cell loss, and (3) amyloid plaque formation. CJD is characterized by progressive dementia and myoclonic seizures, affecting *****s in mid-life. Some patients present sleep disorders, abnormalities of high cortical function, cerebellar and corticospinal disturbances. The disease ends in death after a 3-12 months illness.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Ref.39 Ref.40 Ref.42 Ref.43 Ref.46 Ref.47 Ref.50 Ref.51 Ref.55Fatal familial insomnia (FFI) [MIM:600072]: Autosomal dominant disorder and is characterized by neuronal degeneration limited to selected thalamic nuclei and progressive insomnia.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Ref.35 Ref.38Gerstmann-Straussler disease (GSD) [MIM:137440]: Heterogeneous disorder and was defined as a spinocerebellar ataxia with dementia and plaque-like deposits. GSD incidence is less than 2 per 100 million live births.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.4 Ref.20 Ref.35 Ref.36 Ref.41 Ref.44 Ref.45 Ref.48 Ref.49 Ref.52 Ref.56Huntington disease-like 1 (HDL1) [MIM:603218]: Autosomal dominant, early-onset neurodegenerative disorder with prominent psychiatric features.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20Kuru (KURU) [MIM:245300]: Kuru is transmitted during ritualistic cannibalism, among natives of the New Guinea highlands. Patients exhibit various movement disorders like cerebellar abnormalities, rigidity of the limbs, and clonus. Emotional lability is present, and dementia is conspicuously absent. Death usually occurs from 3 to 12 month after onset.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20Spongiform encephalopathy with neuropsychiatric features (SENF) [MIM:606688]: Autosomal dominant presenile dementia with a rapidly progressive and protracted clinical course. The dementia was characterized clinically by frontotemporal features, including early personality changes. Some patients had memory loss, several showed aggressiveness, hyperorality and verbal stereotypy, others had parkinsonian symptoms.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20
Miscellaneous: This protein is produced by a bicistronic gene which also produces the The alternative prion protein/AltPrP from an overlapping reading frame.The alternative prion protein/AltPrP (AC F7VJQ1) and PRNP have no apparent direct functional relation since a mutation that removes the start codon of the AltPrP has no apparent effect on the
biology of PRNP. In mouse and hamster, the alternative initiation AUG codon is absent and is replaced by a GUG codon.
Sequence similarities: Belongs to the prion family.
