The extracellular domain of Bri2 (ITM2B) binds the ABri peptide (1-23) and amyloid beta-peptide (Abeta1-40): Implications for Bri2 effects on processing of amyloid precursor protein and Abeta aggregation.
In Alzheimer's disease the amyloid beta-peptide (Abeta) aggregates in brain tissue and arteries. Abeta is proteolytically cleaved out from amyloid precursor protein (APP) by different secretases. Recently, the transmembrane protein ITM2B/Bri2, which is expressed in neurons and associated with familial British and Danish dementia, was shown to inhibit APP processing in transfected cells as well as in transgenic mice. Several mechanisms by which Bri2 can interfere with Abeta production and aggregation have been proposed. Herein, we studied recombinant human Bri2 (residues 90-236) containing the extracellular Brichos domain without the ABri23 peptide. Bri2(90-236) binds to ABri23, which suggests that these two parts interact during Bri2 biosynthesis, in line with proposed functions of Brichos domains in other proteins. Moreover, Bri2(90-236) binds Abeta1-40 and inhibits its aggregation and fibril formation. These data suggest a model for how the processing of Bri2 and APP are interrelated.
Peng
Siwei
S
Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, 75123 Uppsala, Sweden. siwei.peng@afb.slu.se
Fitzen
Michael
M
Jörnvall
Hans
H
Johansson
Jan
J
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40)