UniProt functional annotation for P04925



	UniProt functional annotation for P04925

UniProt code: P04925.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Its primary physiological function is unclear. May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May promote myelin homeostasis through acting as an agonist for ADGRG6 receptor. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro) (By similarity). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or ZN(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains (PubMed:12732622, PubMed:16492732, PubMed:19242475, PubMed:19568430). {ECO:0000250|UniProtKB:P04156, ECO:0000269|PubMed:12732622, ECO:0000269|PubMed:16492732, ECO:0000269|PubMed:19242475, ECO:0000269|PubMed:19568430}.

Subunit: 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 (PubMed:11571277). Mislocalized cytosolically exposed PrP interacts with MGRN1; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement (By similarity). Interacts with APP. Interacts with KIAA1191 (By similarity). Interacts with ADGRG6 (PubMed:27501152). {ECO:0000250|UniProtKB:P04156, ECO:0000269|PubMed:11571277, ECO:0000269|PubMed:27501152}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:11571277, ECO:0000269|PubMed:9837873}; Lipid-anchor, GPI-anchor. Golgi apparatus {ECO:0000269|PubMed:11756421}. Note=Targeted to lipid rafts via association with the heparan sulfate chains of GPC1. Colocates, in the presence of Cu(2+), to. vesicles in para- and perinuclear regions, where both proteins undergo internalization. Heparin displaces PRNP from lipid rafts and promotes endocytosis. {ECO:0000269|PubMed:11571277, ECO:0000269|PubMed:12732622, ECO:0000269|PubMed:16923158, ECO:0000269|PubMed:9837873}.

Tissue specificity: Highly expressed in the brain, lung, kidney and heart. Expressed at low levels in the liver and spleen. {ECO:0000269|PubMed:16492732, ECO:0000269|PubMed:19568430}.

Domain: The normal, monomeric form has a mainly alpha-helical structure. The disease-associated, protease-resistant form forms amyloid fibrils containing 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. {ECO:0000250|UniProtKB:P04156}.

Domain: Contains 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. {ECO:0000250|UniProtKB:P04156}.

Ptm: N-glycosylated. {ECO:0000269|PubMed:16492732, ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:19568430}.

Disease: Note=Found in high quantity in the brain of humans and animals infected with degenerative neurological diseases such as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), etc. {ECO:0000305}.

Disruption phenotype: No visible phenotype. Mice develop chronic demyelinating polyneuropathy after 60 weeks. Mice show abnormally low iron levels throughout the body, and are mildly anemic. Iron accumulates in duodenum enterocytes, suggesting impaired transport from the intestine to the blood. Mice deficient for both Prnd and Prnp have the same phenotype as mice lacking Prnd; they are born at the expected Mendelian rate and appear grossly normal and healthy (PubMed:15161660, PubMed:15007175). Females are fertile, but males deficient for both Prnd and Prnp are sterile, in spite of normal mating behavior (PubMed:15161660, PubMed:15007175). Male sterility is due to impaired acrosome reaction (PubMed:15161660). Mutant sperm are able to fertilize oocytes in vitro, but many of the resulting embryos die before the morula stage (PubMed:15161660). Mutant sperm cells have elevated levels of DNA damage and DNA strand breaks, and this may be the cause for embryonic lethality (PubMed:15161660). Aging mice deficient for both Prnd and Prnp do not display loss of cerebellar Purkinje cells or develop ataxia, and do not develop neurological defects (PubMed:15007175). {ECO:0000269|PubMed:15007175, ECO:0000269|PubMed:15161660, ECO:0000269|PubMed:16492732, ECO:0000269|PubMed:19242475, ECO:0000269|PubMed:19568430, ECO:0000269|PubMed:20098419, ECO:0000269|PubMed:8035877, ECO:0000269|PubMed:8637886}.

Similarity: Belongs to the prion family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Its primary physiological function is unclear. May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May promote myelin homeostasis through acting as an agonist for ADGRG6 receptor. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro) (By similarity). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or ZN(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains (PubMed:12732622, PubMed:16492732, PubMed:19242475, PubMed:19568430). {ECO:0000250\|UniProtKB:P04156, ECO:0000269\|PubMed:12732622, ECO:0000269\|PubMed:16492732, ECO:0000269\|PubMed:19242475, ECO:0000269\|PubMed:19568430}.


Subunit:		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 (PubMed:11571277). Mislocalized cytosolically exposed PrP interacts with MGRN1; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement (By similarity). Interacts with APP. Interacts with KIAA1191 (By similarity). Interacts with ADGRG6 (PubMed:27501152). {ECO:0000250\|UniProtKB:P04156, ECO:0000269\|PubMed:11571277, ECO:0000269\|PubMed:27501152}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:11571277, ECO:0000269\|PubMed:9837873}; Lipid-anchor, GPI-anchor. Golgi apparatus {ECO:0000269\|PubMed:11756421}. Note=Targeted to lipid rafts via association with the heparan sulfate chains of GPC1. Colocates, in the presence of Cu(2+), to. vesicles in para- and perinuclear regions, where both proteins undergo internalization. Heparin displaces PRNP from lipid rafts and promotes endocytosis. {ECO:0000269\|PubMed:11571277, ECO:0000269\|PubMed:12732622, ECO:0000269\|PubMed:16923158, ECO:0000269\|PubMed:9837873}.
Tissue specificity:		Highly expressed in the brain, lung, kidney and heart. Expressed at low levels in the liver and spleen. {ECO:0000269\|PubMed:16492732, ECO:0000269\|PubMed:19568430}.
Domain:		The normal, monomeric form has a mainly alpha-helical structure. The disease-associated, protease-resistant form forms amyloid fibrils containing 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. {ECO:0000250\|UniProtKB:P04156}.
Domain:		Contains 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. {ECO:0000250\|UniProtKB:P04156}.
Ptm:		N-glycosylated. {ECO:0000269\|PubMed:16492732, ECO:0000269\|PubMed:19349973, ECO:0000269\|PubMed:19568430}.
Disease:		Note=Found in high quantity in the brain of humans and animals infected with degenerative neurological diseases such as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), etc. {ECO:0000305}.
Disruption phenotype:		No visible phenotype. Mice develop chronic demyelinating polyneuropathy after 60 weeks. Mice show abnormally low iron levels throughout the body, and are mildly anemic. Iron accumulates in duodenum enterocytes, suggesting impaired transport from the intestine to the blood. Mice deficient for both Prnd and Prnp have the same phenotype as mice lacking Prnd; they are born at the expected Mendelian rate and appear grossly normal and healthy (PubMed:15161660, PubMed:15007175). Females are fertile, but males deficient for both Prnd and Prnp are sterile, in spite of normal mating behavior (PubMed:15161660, PubMed:15007175). Male sterility is due to impaired acrosome reaction (PubMed:15161660). Mutant sperm are able to fertilize oocytes in vitro, but many of the resulting embryos die before the morula stage (PubMed:15161660). Mutant sperm cells have elevated levels of DNA damage and DNA strand breaks, and this may be the cause for embryonic lethality (PubMed:15161660). Aging mice deficient for both Prnd and Prnp do not display loss of cerebellar Purkinje cells or develop ataxia, and do not develop neurological defects (PubMed:15007175). {ECO:0000269\|PubMed:15007175, ECO:0000269\|PubMed:15161660, ECO:0000269\|PubMed:16492732, ECO:0000269\|PubMed:19242475, ECO:0000269\|PubMed:19568430, ECO:0000269\|PubMed:20098419, ECO:0000269\|PubMed:8035877, ECO:0000269\|PubMed:8637886}.
Similarity:		Belongs to the prion family. {ECO:0000305}.