integral membrane protein 2B; transmembrane protein BRI; protein E25B (ITM2B, BRI, BRI2)

Function

• protease inhibitor
• plays a role in APP processing regulating physiological production of beta amyloid peptide
• restricts docking of gamma-secretase to APP & access of alpha-secretase & beta-secretase to their cleavage APP sequence
• the C-terminal part of the ectodomain is processed by furin & related proteases producing a secreted peptide of 4 to 5 kD
• for the ABRI & ADAN variants, the C-terminal secreted peptide is larger & may produce amyloid fibrils responsible for neuronal dysfunction & dementia
• the remaining part of the ectodomain containing the BRICHOS domain is cleaved by ADAM10 & is secreted as a peptide of 25 kD
• the membrane-bound N-terminal fragment (NTF) of 22 kD is further proteolytically processed by SPPL2A & SPPL2B through regulated intramembrane proteolysis producing a secreted peptide (BRI2C) & an intracellular domain (ICD) released in the cytosol
• interacts with SPPL2A & SPPL2B
• interacts with APP

Structure

• homodimer; disulfide-linked
• belongs to the ITM2 family
• contains 1 BRICHOS domain

Compartment

• Golgi membrane, cell membrane
• single-pass type 2 membrane protein

Expression

expressed in brain & in other tissues

Pathology

• defects in ITM2B are a cause of
  • familial British dementia via generation of ABri amyloid
  • familial Danish dementia via generation of ADan amyloid

More general terms

• ITM2 protein

Database

• OMIM: https://mirror.omim.org/entry/603904
• OMIM: https://mirror.omim.org/entry/117300
• OMIM: https://mirror.omim.org/entry/176500
• UniProt: http://www.uniprot.org/uniprot/Q9Y287.html
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=9445