BRI2 homodimerizes with the involvement of intermolecular disulfide bonds.
Familial British and Familial Danish Dementia (FBD and FDD) are two dominantly inherited neurodegenerative diseases that present striking similarities with Alzheimer's disease. The genetic defects underlying those dementias are mutations in the gene that encodes for BRI2 protein. Cleavage of mutated BRI2 by furin releases the peptides ABri or ADan, which accumulate in the brains of patients. BRI2 normal function is yet unknown. To unwind aspects of its cellular role, we investigated the possibility that BRI2 forms dimers, based on structural elements of the protein, the GXXXG motif within its transmembrane domain and the odd number of cysteine residues. We found that BRI2 dimerizes in cells and that dimers are held via non-covalent interactions and via disulfide bridges between the cysteines at position 89. Additionally, we showed that BRI2 dimers are formed in the ER and appear at the cell surface. Finally, BRI2 dimers were found to exist in mouse brain. Revealing the physiological properties of BRI2 is critical in the elucidation of the deviations that lead to neurodegeneration.
Tsachaki
Maria
M
Division of Animal & Human Physiology, Department of Biology, National & Kapodistrian University of Athens, 157 84 Panepistimiopolis, Ilisia, Athens, Greece. mtsachaki@yahoo.gr
Ghiso
Jorge
J
Rostagno
Agueda
A
Efthimiopoulos
Spiros
S
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019281:Dimerization; D004220:Disulfides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D004220:Disulfides; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D003545:Cysteine