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MGP003905

UniProt Annotations

Entry Information
Gene Nameintegral membrane protein 2B
Protein EntryITM2B_HUMAN
UniProt IDQ9Y287
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q9Y287-1; Sequence=Displayed; Name=2; IsoId=Q9Y287-2; Sequence=VSP_055326; Note=No experimental confirmation available.;
DiseaseCerebral amyloid angiopathy, ITM2B-related 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. Note=The disease is caused by mutations affecting the gene represented in this entry. A single base substitution at the stop codon of ITM2B generates a 277-residue precursor that is cleaved at the normal furin processing site to generate the ABri amyloidogenic peptide (PubMed:10391242). ABri accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. ABri peptide variant forms fibrils in vitro (PubMed:10526337). {ECO:0000269|PubMed:10391242, ECO:0000269|PubMed:10526337}.
DiseaseCerebral amyloid angiopathy, ITM2B-related 2 (CAA-ITM2B2) [MIM:117300]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry. A decamer duplication in the 3' region of ITM2B results in the production of the ADan amyloidogenic peptide (PubMed:10781099). ADan is generated by cleavage of the mutated precursor at the normal furin processing site. ADan accumulates in the brain and produces amyloid fibrils responsible for neuronal dysfunction and dementia. {ECO:0000269|PubMed:10781099}.
DiseaseRetinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities (RDGCA) [MIM:616079]: An autosomal dominant retinal dystrophy characterized by inner retinal dysfunction in association with ganglion cell abnormalities. Clinical features include mild photophobia, progressive loss of central vision, night blindness, and hyperreflectivity of nerve and ganglion cell layers. {ECO:0000269|PubMed:24026677}. Note=The disease is caused by mutations affecting the gene represented in this entry.
FunctionBri23 peptide prevents aggregation of APP beta-amyloid protein 42 peptide into toxic oligomers.
FunctionMature BRI2 (mBRI2) functions as a modulator of the beta-amyloid A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed beta- amyloid protein 40 and beta-amyloid protein 42.
FunctionPlays a regulatory role in the processing of the beta- amyloid A4 precursor protein (APP) and acts as an inhibitor of the beta-amyloid peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites.
PtmGlycosylation at Asn-170 is important for cell surface localization, but doesn't affect furin- and ADAM10-induced proteolytic processing. {ECO:0000269|PubMed:21752865}.
PtmThe ectodomain C-terminal part of the imBRI2 is processed by furin producing a secreted Bri23 peptide and a mature BRI2, membrane form (mBRI2). The remaining part of the ectodomain of mBRI2 containing the BRICHOS domain is cleaved by ADAM10 and is secreted (BRI2C, soluble form). The membrane-bound N-terminal fragment (BRI2C, membrane form) is further proteolytically processed by SPPL2A and SPPL2B through regulated intramembrane proteolysis producing a secreted C-peptide and a BRI2 intracellular domain (BRI2 ICD) released in the cytosol. Shedding by ADAM10 facilitates intramembrane cleavage but is not absolutely required for BRI2 ICD generation.
SimilarityBelongs to the ITM2 family. {ECO:0000305}.
SimilarityContains 1 BRICHOS domain. {ECO:0000255|PROSITE- ProRule:PRU00255}.
Subcellular LocationBri23 peptide: Secreted. Note=Detected in the cerebral spinal fluid (CSF).
Subcellular LocationBRI2C, soluble form: Secreted.
Subcellular LocationBRI2, membrane form: Cell membrane; Single- pass type II membrane protein. Endosome membrane; Single-pass type II membrane protein. Note=Mature BRI2 (mBRI2) needs to be transported from the endoplasmic reticulum compartment to the cell membrane in order to be able to inhibit APP processing.
Subcellular LocationIntegral membrane protein 2B: Golgi apparatus membrane; Single-pass type II membrane protein. Note=Immature BRI2 (imBRI2) is cleaved by furin in the Golgi into mBRI2 and a Bri23 peptide. mBRI2 is transported to the plasma membrane and Bri23 peptide is secreted.
SubunitHomodimer; disulfide-linked. Interacts with SPPL2A and SPPL2B. Interacts with APP. Mature BRI2 (mBRI2) interacts with the APP amyloid beta A4 protein; the interaction occurs at the cell surface and in the endocytic compartments and enable alpha- and beta-secretase-induced APP cleavage inhibition. Mature BRI2 (mBRI2) interacts with the APP C99; the interaction occurs in the endocytic compartments and enable gamma-secretase-induced C99 cleavage inhibition. May form heterodimers with Bri23 peptide and APP beta-amyloid protein 40. {ECO:0000269|PubMed:15983050, ECO:0000269|PubMed:16027166, ECO:0000269|PubMed:17965014, ECO:0000269|PubMed:18440095, ECO:0000269|PubMed:19748705, ECO:0000269|PubMed:20036644, ECO:0000269|PubMed:22170863}.
Tissue SpecificityUbiquitous. Expressed in brain.
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/itm2b/";
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