P23907 (PRIO_SHEEP) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Major prion protein
Short name=PrP

Alternative name(s):
CD_antigen=CD230

Gene names

Name:	PRNP
Synonyms:	PRP, SIP

Organism

Ovis aries (Sheep)

Taxonomic identifier

9940 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Caprinae › Ovis

Protein attributes

Sequence length	256 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	The function of PrP is still under debate. 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 By similarity. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro) By similarity.
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 APP, GRB2, ERI3/PRNPIP and SYN1. Mislocalized cytosolically exposed PrP interacts with MGRN1; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement By similarity. Ref.14
Subcellular location	Cell membrane; Lipid-anchor › GPI-anchor. Golgi apparatus By similarity.
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 By similarity. Ref.14 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 By similarity. Ref.14
Involvement in disease	Note=Polymorphism at position 171 may be related to the alleles of scrapie incubation-control (SIC) gene in this species. 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. Note=Scrapie is a transmissible neurodegenerative disorder of sheep and goats. Most sheep that contract the disease naturally die between 24 and 50 months of age. The incubation period in sheep depends on the strain(s) of the infecting pathogen, sheep age at exposure, and the sheep genotype. The survival time is mainly determined by a single genetic locus, SIP, which has two alleles, susceptible (sa) and resistant (pa). Short incubation period is conferred by the partially dominant sa allele. Scrapie can be spread between flockmates, or it can be transmitted from an infected ewe to its lamb.
Sequence similarities	Belongs to the prion family.

Ontologies

Keywords
Cellular component	Amyloid Cell membrane Golgi apparatus Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Repeat Signal
Ligand	Copper Metal-binding Zinc
Molecular function	Prion
PTM	Disulfide bond GPI-anchor Glycoprotein Lipoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	protein homooligomerization Inferred from electronic annotation. Source: InterPro
Cellular component	Golgi apparatus Inferred from electronic annotation. Source: UniProtKB-SubCell anchored to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	copper ion binding Inferred from sequence or structural similarity. Source: UniProtKB microtubule binding Inferred from sequence or structural similarity. Source: AgBase
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Chain

25 – 233

209

Major prion protein

PRO_0000025727

Propeptide

234 – 256

23

Removed in mature form Potential

PRO_0000025728

Regions

Repeat

54 – 62

9

1

Repeat

63 – 70

8

2

Repeat

71 – 78

8

3

Repeat

79 – 86

8

4

Repeat

87 – 95

9

5

Region

25 – 233

209

Interaction with GRB2, ERI3 and SYN1 By similarity

Region

54 – 95

42

5 X 8 AA tandem repeats of P-H-G-G-G-W-G-Q

Sites

Metal binding

64

1

Copper or zinc 1 By similarity

Metal binding

65

1

Copper or zinc 1; via amide nitrogen By similarity

Metal binding

66

1

Copper or zinc 1; via amide nitrogen and carbonyl oxygen By similarity

Metal binding

72

1

Copper or zinc 2 By similarity

Metal binding

73

1

Copper or zinc 2; via amide nitrogen By similarity

Metal binding

74

1

Copper or zinc 2; via amide nitrogen and carbonyl oxygen By similarity

Metal binding

80

1

Copper or zinc 3 By similarity

Metal binding

81

1

Copper or zinc 3; via amide nitrogen By similarity

Metal binding

82

1

Copper or zinc 3; via amide nitrogen and carbonyl oxygen By similarity

Metal binding

88

1

Copper or zinc 4 By similarity

Metal binding

89

1

Copper or zinc 4; via amide nitrogen By similarity

Metal binding

90

1

Copper or zinc 4; via amide nitrogen and carbonyl oxygen By similarity

Amino acid modifications

Lipidation

233

1

GPI-anchor amidated alanine Potential

Glycosylation

184

1

N-linked (GlcNAc...) Probable

Glycosylation

200

1

N-linked (GlcNAc...) Probable

Disulfide bond

182 ↔ 217

Natural variations

Natural variant

112

1

M → T. Ref.16

Natural variant

136

1

A → V in scrapie; short incubation; sA allele. Ref.15 Ref.16 Ref.17

Natural variant

137

1

M → T. Ref.18

Natural variant

141

1

L → F. Ref.6 Ref.8 Ref.18

Natural variant

154

1

R → H. Ref.15 Ref.16 Ref.17

Natural variant

171

1

R → H in scrapie; low incidence. Ref.17

Natural variant

171

1

R → Q Linked to susceptibility to scrapie. Ref.1 Ref.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.8 Ref.9 Ref.15

Natural variant

211

1

R → Q. Ref.8 Ref.18

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

256

Helix Strand Turn

Details...

Helix

147 – 155

9

Helix

157 – 159

3

Helix

169 – 171

3

Beta strand

173 – 175

3

Helix

176 – 196

21

Helix

203 – 229

27

Sequences

	Sequence		Length	Mass (Da)
	P23907 [UniParc]. Last modified November 1, 1991. Version 1. Checksum: 7FFBEA6C6FDBF8BB	FASTA	256	27,915
	10 20 30 40 50 60 MVKSHIGSWI LVLFVAMWSD VGLCKKRPKP GGGWNTGGSR YPGQGSPGGN RYPPQGGGGW 70 80 90 100 110 120 GQPHGGGWGQ PHGGGWGQPH GGGWGQPHGG GGWGQGGSHS QWNKPSKPKT NMKHVAGAAA 130 140 150 160 170 180 AGAVVGGLGG YMLGSAMSRP LIHFGNDYED RYYRENMYRY PNQVYYRPVD RYSNQNNFVH 190 200 210 220 230 240 DCVNITVKQH TVTTTTKGEN FTETDIKIME RVVEQMCITQ YQRESQAYYQ RGASVILFSS 250 PPVILLISFL IFLIVG

References

[1]	"Two alleles of a neural protein gene linked to scrapie in sheep." Goldmann W., Hunter N., Foster J.D., Salbaum J.M., Beyreuther K., Hope J. Proc. Natl. Acad. Sci. U.S.A. 87:2476-2480(1990) [PubMed: 1969635] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-171. Strain: Suffolk. Tissue: Spleen.
[2]	"Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie." Westaway D., Zuliani V., Cooper C.M., da Costa M., Neuman S., Jenny A.L., Detwiler L., Prusiner S.B. Genes Dev. 8:959-969(1994) [PubMed: 7926780] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-171. Strain: Suffolk. Tissue: Brain.
[3]	"Complete genomic sequence and analysis of the prion protein gene region from three mammalian species." Lee I.Y., Westaway D., Smit A.F.A., Wang K., Seto J., Chen L., Acharya C., Ankener M., Baskin D., Cooper C., Yao H., Prusiner S.B., Hood L.E. Genome Res. 8:1022-1037(1998) [PubMed: 9799790] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-171. Tissue: Brain.
[4]	"PrP (prion) gene expression in sheep may be modulated by alternative polyadenylation of its messenger RNA." Goldmann W., O'Neill G., Cheung F., Charleson F., Ford P., Hunter N. J. Gen. Virol. 80:2275-2283(1999) [PubMed: 10466827] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-171.
[5]	"Identification of a novel ovine PrP polymorphism and scrapie-resistant genotypes for St. Croix White and a related composite breed." Seabury C.M., Derr J.N. Cytogenet. Genome Res. 102:85-88(2003) [PubMed: 14970684] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-171.
[6]	"Prion protein gene polymorphisms in healthy and scrapie affected sheep in Greece." Billinis C., Psychas V., Leontides L., Spyrou V., Argyroudis S., Vlemmas I., Leontides S., Sklaviadis T., Papadopoulos O. J. Gen. Virol. 85:547-554(2004) [PubMed: 14769911] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS PHE-141 AND GLN-171.
[7]	Inoue S., Watanabe A., Horiuchi M., Ishiguro N., Shinagawa M. Submitted (SEP-1994) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Liver.
[8]	"PrP allelic variants associated with natural scrapie." Bossers A. Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS PHE-141; GLN-171 AND GLN-211.
[9]	"A set of genotyping controls for 15 haplotype combinations of ovine PRNP codons 136, 154, and 171." Heaton M.P., Leymaster K.A., Clawson M.L., Laegreid W.W. Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLN-171.
[10]	"The epididymal soluble prion protein forms a high-molecular-mass complex in association with hydrophobic proteins." Ecroyd H., Belghazi M., Dacheux J.-L., Gatti J.-L. Biochem. J. 392:211-219(2005) [PubMed: 16029166] [Abstract] Cited for: IDENTIFICATION IN COMPLEX WITH CES5A; CLU; BPI; MANBA AND GLB1. Tissue: Epididymis.
[11]	"The crystal structure of the globular domain of sheep prion protein." Haire L.F., Whyte S.M., Vasisht N., Gill A.C., Verma C., Dodson E.J., Dodson G.G., Bayley P.M. J. Mol. Biol. 336:1175-1183(2004) [PubMed: 15037077] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 128-233.
[12]	"Insight into the PrPC-->PrPSc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants." Eghiaian F., Grosclaude J., Lesceu S., Debey P., Doublet B., Treguer E., Rezaei H., Knossow M. Proc. Natl. Acad. Sci. U.S.A. 101:10254-10259(2004) [PubMed: 15240887] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.56 ANGSTROMS) OF 115-234 IN COMPLEX WITH ANTIBODY.
[13]	"Prion protein NMR structures of cats, dogs, pigs, and sheep." Lysek D.A., Schorn C., Nivon L.G., Esteve-Moya V., Christen B., Calzolai L., von Schroetter C., Fiorito F., Herrmann T., Guentert P., Wuethrich K. Proc. Natl. Acad. Sci. U.S.A. 102:640-645(2005) [PubMed: 15647367] [Abstract] Cited for: STRUCTURE BY NMR OF 124-234.
[14]	"Prion fibrillization is mediated by a native structural element that comprises helices H2 and H3." Adrover M., Pauwels K., Prigent S., de Chiara C., Xu Z., Chapuis C., Pastore A., Rezaei H. J. Biol. Chem. 285:21004-21012(2010) [PubMed: 20375014] [Abstract] Cited for: STRUCTURE BY NMR OF 167-234, SUBUNIT, DOMAIN.
[15]	"Different scrapie-associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the Sip gene." Goldmann W., Hunter N., Benson G., Foster J.D., Hope J. J. Gen. Virol. 72:2411-2417(1991) [PubMed: 1681027] [Abstract] Cited for: VARIANTS SCRAPIE VAL-136; HIS-154 AND GLN-171.
[16]	"PrP polymorphisms associated with natural scrapie discovered by denaturing gradient gel electrophoresis." Laplanche J.-L., Chatelain J., Westaway D., Thomas S., Dussaucy M., Brugere-Picoux J., Launay J.-M. Genomics 15:30-37(1993) [PubMed: 8094373] [Abstract] Cited for: VARIANTS SCRAPIE THR-112; VAL-136 AND HIS-154.
[17]	"Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie." Belt P.B.G.M., Muileman I.H., Schreuder B.E.C., Bos-De Ruijter J., Gielkens A.L.J., Smits M.A. J. Gen. Virol. 76:509-517(1995) [PubMed: 7897344] [Abstract] Cited for: VARIANTS SCRAPIE VAL-136 AND HIS-171, VARIANT HIS-154.
[18]	"PrP genotype contributes to determining survival times of sheep with natural scrapie." Bossers A., Schreuder B.E.C., Muileman I.H., Belt P.B.G.M., Smits M.A. J. Gen. Virol. 77:2669-2673(1996) [PubMed: 8887505] [Abstract] Cited for: VARIANTS THR-137; PHE-141 AND GLN-211.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M31313 Genomic DNA. Translation: AAB97765.1.
X79912 Genomic DNA. Translation: CAA56283.1.
U67922 Genomic DNA. Translation: AAC78726.1.
AJ223072 Genomic DNA. Translation: CAA11073.1.
AY350241 Genomic DNA. Translation: AAR14214.1.
AY350242 Genomic DNA. Translation: AAR14215.1.
AY350243 Genomic DNA. Translation: AAR14216.1.
AY350245 Genomic DNA. Translation: AAR14218.1.
AY350246 Genomic DNA. Translation: AAR14219.1.
AY350248 Genomic DNA. Translation: AAR14221.1.
AY350249 Genomic DNA. Translation: AAR14222.1.
AY350250 Genomic DNA. Translation: AAR14223.1.
AY350254 Genomic DNA. Translation: AAR14227.1.
AY350256 Genomic DNA. Translation: AAR14229.1.
AY350257 Genomic DNA. Translation: AAR14230.1.
AY350261 Genomic DNA. Translation: AAR14234.1.
AY350264 Genomic DNA. Translation: AAR14237.1.
AY350267 Genomic DNA. Translation: AAR14240.1.
AY350268 Genomic DNA. Translation: AAR14241.1.
AY350271 Genomic DNA. Translation: AAR14244.1.
AY350272 Genomic DNA. Translation: AAR14245.1.
AY350273 Genomic DNA. Translation: AAR14246.1.
AY350275 Genomic DNA. Translation: AAR14248.1.
AJ567984 Genomic DNA. Translation: CAE00186.1.
AJ567985 Genomic DNA. Translation: CAE00187.1.
AJ567986 Genomic DNA. Translation: CAE00188.2.
D38179 Genomic DNA. Translation: BAA07376.1.
AJ000680 Genomic DNA. Translation: CAA04235.1.
AJ000681 Genomic DNA. Translation: CAA04236.1.
AJ000736 Genomic DNA. Translation: CAA04274.1.
AJ000739 Genomic DNA. Translation: CAA04277.1.
AY907689 Genomic DNA. Translation: AAW88336.1.
AY907690 Genomic DNA. Translation: AAW88337.1.
AY907691 Genomic DNA. Translation: AAW88338.1.

RefSeq

NP_001009481.1. NM_001009481.1.

UniGene

Oar.765.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1G04	NMR	-	A	145-169	[»]
1M25	NMR	-	A	145-169	[»]
1S4T	NMR	-	A	138-158	[»]
1TPX	X-ray	2.56	A	114-234	[»]
1TQB	X-ray	2.55	A	127-228	[»]
1TQC	X-ray	2.80	A	127-228	[»]
1UW3	X-ray	2.04	A	128-233	[»]
1XYU	NMR	-	A	124-234	[»]
1Y2S	NMR	-	A	124-234	[»]
2KTM	NMR	-	A	167-234	[»]

ProteinModelPortal

P23907.

SMR

P23907. Positions 1-30, 127-228.

ModBase

Search...

Protein family/group databases

TCDB

1.C.48.1.1. prion peptide fragment (PrP-F) family.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

493887.

Organism-specific databases

CTD

5621.

Phylogenomic databases

HOVERGEN

HBG008260.

Family and domain databases

InterPro

IPR000817. Prion.
IPR022416. Prion/Doppel_prot_b-ribbon_dom.
[Graphical view]

Gene3D

G3DSA:1.10.790.10. Prion. 1 hit.

PANTHER

PTHR11522. Prion. 1 hit.

Pfam

PF00377. Prion. 1 hit.
[Graphical view]

PRINTS

PR00341. PRION.

SMART

SM00157. PRP. 1 hit.
[Graphical view]

SUPFAM

SSF54098. Prion. 1 hit.

PROSITE

PS00291. PRION_1. 1 hit.
PS00706. PRION_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Entry information

Entry name

PRIO_SHEEP

Accession

Primary (citable) accession number: P23907
Secondary accession number(s): Q5ECG0 , Q6V638, Q6V654, Q712W2, Q712W3, Q7JGT4

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1991
Last sequence update:	November 1, 1991
Last modified:	June 28, 2011
This is version 94 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program