Familial British dementia: expression and metabolism of BRI.
Vidal et al. (1999. Nature 399: 776-778) discovered that the underlying genetic lesion in familial British dementia (FBD) is a T-A transversion at the termination codon of a membrane protein, termed BRI. The mutation creates an arginine codon; translational read-through generates a novel protein, termed BRI-L, that is extended by 11 amino acids at the carboxyl-terminus. BRI-L is the precursor of the ABri peptide, a component of amyloid deposits in FBD brain. We demonstrate that both BRI and its mutant counterpart are constitutively processed by furin, resulting in the secretion of carboxyl-terminal peptide derivatives that correspond to all, or part of, ABri. Notably, elevated levels of peptides are generated from the mutant BRI precursor, suggesting that subtle conformational alterations at the carboxyl-terminus may influence furin-mediated processing. We have examined BRI/BRI-L processing by other members of the prohormone convertase (PC) family (PACE4, LPC, PC 5/6) and found that these enzymes also process BRI, albeit inefficiently. Moreover, BRI-L processing by the other PC members is severely compromised. Finally, our electron microscopic studies reveal that synthetic ABri peptides assemble into insoluble beta-pleated fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates amyloidogenic peptides that initiate the pathogenesis of FBD.
Kim
S H
SH
Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Abbott 316, 947 East 58th Street, Chicago, IL 60637, USA.
Wang
R
R
Gordon
D J
DJ
Bass
J
J
Steiner
D F
DF
Thinakaran
G
G
Lynn
D G
DG
Meredith
S C
SC
Sisodia
S S
SS
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000682:Amyloid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D018388:Codon, Terminator; D003704:Dementia / Q000235:genetics*; D045683:Furin; D006801:Humans; D008322:Mammals; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013381:Subtilisins / Q000378:metabolism; D014162:Transfection; D006113:United Kingdom
D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D018388:Codon, Terminator; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013381:Subtilisins; D045683:Furin