Q9Y287 (ITM2B_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Integral membrane protein 2B

Alternative name(s):
Protein E25B
Transmembrane protein BRI

Cleaved into the following chain:

1. ABri/ADan amyloid peptide

Gene names

Name:	ITM2B
Synonyms:	BRI, BRI2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	266 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	Functions as a protease inhibitor. Plays a role in APP processing regulating the physiological production of the beta amyloid peptide. Restricts docking of gamma-secretase to APP and access of alpha- and beta-secretase to their cleavage APP sequence. Ref.6 Ref.8
Subunit structure	Homodimer; disulfide-linked. Interacts with SPPL2A and SPPL2B. Interacts with APP. Ref.6 Ref.7 Ref.9
Subcellular location	Golgi apparatus membrane; Single-pass type II membrane protein. Cell membrane; Single-pass type II membrane protein Ref.7 Ref.9.
Tissue specificity	Expressed in brain and in other tissues.
Post-translational modification	The C-terminal part of the ectodomain is processed by furin and related proteases producing a secreted peptide of 4 to 5 kDa. For the ABRI and ADAN variants the C-terminal secreted peptide is larger and may produce amyloid fibrils responsible for neuronal dysfunction and dementia. The remaining part of the ectodomain containing the BRICHOS domain is cleaved by ADAM10 and is secreted as a peptide of 25 kDa. The membrane-bound N-terminal fragment (NTF) of 22 kDa is further proteolytically processed by SPPL2A and SPPL2B through regulated intramembrane proteolysis producing a secreted peptide (BRI2C) and an intracellular domain (ICD) released in the cytosol. Ref.7
Involvement in disease	Defects in ITM2B are a cause of cerebral amyloid angiopathy ITM2B-related type 1 (CAA-ITM2B1) [MIM:176500]. A disorder characterized by amyloid deposition in the walls of cerebral blood vessels and neurodegeneration in the central nervous system. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Clinical features include progressive mental deterioration, spasticity and muscular rigidity. Ref.1 Defects in ITM2B are a cause of cerebral amyloid angiopathy ITM2B-related type 2 (CAA-ITM2B2) [MIM:117300]; also known as heredopathia ophthalmo-oto-encephalica. A disorder characterized by amyloid deposition in the walls of the blood vessels of the cerebrum, choroid plexus, cerebellum, spinal cord and retina. Plaques and neurofibrillary tangles are observed in the hippocampus. Clinical features include progressive ataxia, dementia, cataracts and deafness.
Sequence similarities	Belongs to the ITM2 family. Contains 1 BRICHOS domain.

Ontologies

Keywords
Cellular component	Amyloid Cell membrane Golgi apparatus Membrane
Disease	Amyloidosis Deafness Disease mutation
Domain	Signal-anchor Transmembrane Transmembrane helix
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	nervous system development Traceable author statement. Source: ProtInc
Cellular component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular region Traceable author statement. Source: Reactome integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW nucleus Inferred from direct assay. Source: HPA plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	beta-amyloid binding Inferred from physical interaction. Source: BHF-UCL
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 266	266	Integral membrane protein 2B		PRO_0000045840
	Peptide	244 – 266	23	ABri/ADan amyloid peptide		PRO_0000016545
Regions
	Topological domain	1 – 54	54	Cytoplasmic Potential
	Transmembrane	55 – 75	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	76 – 266	191	Lumenal Potential
	Domain	137 – 231	95	BRICHOS
Amino acid modifications
	Glycosylation	170	1	N-linked (GlcNAc...) Potential
	Disulfide bond	89		Interchain Ref.9
	Disulfide bond	164 ↔ 223		Probable
	Disulfide bond	248 ↔ 265		Probable
Natural variations
	Natural variant	266	1	S → FNLFLNSQEKHY in CAA-ITM2B2; amyloid ADan. Ref.1		VAR_010240
	Natural variant	266	1	S → SRTVKKNIIEEN in CAA-ITM2B1; amyloid ABri.		VAR_010239

Sequences

	Sequence		Length	Mass (Da)
	Q9Y287 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: 3A7D8CA259F1F627	FASTA	266	30,338
	10 20 30 40 50 60 MVKVTFNSAL AQKEAKKDEP KSGEEALIIP PDAVAVDCKD PDDVVPVGQR RAWCWCMCFG 70 80 90 100 110 120 LAFMLAGVIL GGAYLYKYFA LQPDDVYYCG IKYIKDDVIL NEPSADAPAA LYQTIEENIK 130 140 150 160 170 180 IFEEEEVEFI SVPVPEFADS DPANIVHDFN KKLTAYLDLN LDKCYVIPLN TSIVMPPRNL 190 200 210 220 230 240 LELLINIKAG TYLPQSYLIH EHMVITDRIE NIDHLGFFIY RLCHDKETYK LQRRETIKGI 250 260 QKREASNCFA IRHFENKFAV ETLICS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A stop-codon mutation in the BRI gene associated with familial British dementia." Vidal R., Frangione B., Rostagno A., Mead S., Revesz T., Plant G., Ghiso J. Nature 399:776-781(1999) [PubMed: 10391242] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CAA-ITM2B1 ARG-THR-VAL-LYS-LYS-ASN-ILE-ILE-GLU-GLU-ASN-266 INS. Tissue: Pituitary.
[2]	"A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred." Vidal R., Revesz T., Rostagno A., Kim E., Holton J.L., Bek T., Bojsen-Moeller M., Braendgaard H., Plant G., Ghiso J., Frangione B. Proc. Natl. Acad. Sci. U.S.A. 97:4920-4925(2000) [PubMed: 10781099] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CAA-ITM2B2 SER-266 DELINS PHE-ASN-LEU-PHE-LEU-ASN-SER-GLN-GLU-LYS-HIS-TYR.
[3]	"Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning." Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M. , Zhou J., Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L. Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000) [PubMed: 10931946] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pituitary.
[4]	NIEHS SNPs program Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[6]	"The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production." Matsuda S., Giliberto L., Matsuda Y., Davies P., McGowan E., Pickford F., Ghiso J., Frangione B., D'Adamio L. J. Biol. Chem. 280:28912-28916(2005) [PubMed: 15983050] [Abstract] Cited for: FUNCTION, INTERACTION WITH APP.
[7]	"Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b." Martin L., Fluhrer R., Reiss K., Kremmer E., Saftig P., Haass C. J. Biol. Chem. 283:1644-1652(2008) [PubMed: 17965014] [Abstract] Cited for: SUBCELLULAR LOCATION, TOPOLOGY, PROTEOLYTIC PROCESSING, INTERACTION WITH SPPL2A AND SPPL2B.
[8]	"BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate." Matsuda S., Giliberto L., Matsuda Y., McGowan E.M., D'Adamio L. J. Neurosci. 28:8668-8676(2008) [PubMed: 18753367] [Abstract] Cited for: FUNCTION.
[9]	"BRI2 homodimerizes with the involvement of intermolecular disulfide bonds." Tsachaki M., Ghiso J., Rostagno A., Efthimiopoulos S. Neurobiol. Aging 31:88-98(2010) [PubMed: 18440095] [Abstract] Cited for: SUBCELLULAR LOCATION, SUBUNIT, DISULFIDE BONDS.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF152462 mRNA. Translation: AAD45280.1. AF246221 mRNA. Translation: AAF66130.1. AF092128 mRNA. Translation: AAD40370.1. AY341247 Genomic DNA. Translation: AAP88930.1. BC000554 mRNA. Translation: AAH00554.1.
IPI	IPI00031821.
RefSeq	NP_068839.1. NM_021999.4.
UniGene	Hs.643683.
3D structure databases
ProteinModelPortal	Q9Y287.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Y287. 4 interactions.
STRING	Q9Y287.
Polymorphism databases
DMDM	12643343.
Proteomic databases
PeptideAtlas	Q9Y287.
PRIDE	Q9Y287.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000378565; ENSP00000367828; ENSG00000136156.
GeneID	9445.
KEGG	hsa:9445.
UCSC	uc001vbz.2. human.
Organism-specific databases
CTD	9445.
GeneCards	GC13P048807.
H-InvDB	HIX0011308. HIX0130617.
HGNC	HGNC:6174. ITM2B.
HPA	HPA029292.
MIM	117300. phenotype. 176500. phenotype. 603904. gene.
neXtProt	NX_Q9Y287.
Orphanet	97345. Familial dementia, British type.
GenAtlas	Search...
Phylogenomic databases
GeneTree	ENSGT00390000005162.
HOGENOM	HBG446485.
HOVERGEN	HBG059373.
InParanoid	Q9Y287.
OMA	TIRGIQK.
OrthoDB	EOG48D0WD.
PhylomeDB	Q9Y287.
Enzyme and pathway databases
Reactome	REACT_75925. Amyloids.
Gene expression databases
ArrayExpress	Q9Y287.
Bgee	Q9Y287.
CleanEx	HS_ITM2B.
Genevestigator	Q9Y287.
GermOnline	ENSG00000136156. Homo sapiens.
Family and domain databases
InterPro	IPR007084. BRICHOS_dom. [Graphical view]
Pfam	PF04089. BRICHOS. 1 hit. [Graphical view]
SMART	SM01039. BRICHOS. 1 hit. [Graphical view]
PROSITE	PS50869. BRICHOS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	35380.
SOURCE	Search...

Entry information

Entry name

ITM2B_HUMAN

Accession

Primary (citable) accession number: Q9Y287
Secondary accession number(s): Q9NYH1

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 24, 2001
Last sequence update:	November 1, 1999
Last modified:	January 25, 2012
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.