ITM2B

Amyloid precursor proteins are processed by beta-secretase and gamma-secretase to produce beta-amyloid peptides which form the characteristic plaques of Alzheimer disease. This gene encodes a transmembrane protein which is processed at the C-terminus by f

integral membrane protein 2B

Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta 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.
Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42.
Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers.

Negative regulation of amyloid precursor protein biosynthetic processManual Assertion Based On ExperimentIDA:UniProtKB
Nervous system developmentManual Assertion Based On ExperimentTAS:ProtInc

Integral membrane protein 2B: Golgi apparatus membrane. 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.
BRI2, membrane form: Cell membrane; Endosome membrane. 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.
Bri23 peptide: Secreted. Detected in the cerebral spinal fluid (CSF).
BRI2C, soluble form: Secreted

Cerebral amyloid angiopathy, ITM2B-related 1 (CAA-ITM2B1):
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.
Cerebral amyloid angiopathy, ITM2B-related 2 (CAA-ITM2B2):
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.
Retinal dystrophy with inner retinal dysfunction and ganglion cell abnormalities (RDGCA):
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.

Cytoplasmic: 1-54
Helical: 55-75
Lumenal: 76-266

The 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.
Glycosylation at Asn-170 is important for cell surface localization, but doesn't affect furin- and ADAM10-induced proteolytic processing.