Beta-amyloid precursor protein cleavage by a membrane-bound protease.
The principal component of amyloid plaques in Alzheimer disease is beta-amyloid protein, an approximately 4-kDa peptide derived from amyloid precursor proteins. Previous studies have established that amyloid precursor proteins are secreted after proteolytic cleavage within the beta-amyloid peptide. The present investigation documents that, in cultured cells, amyloid precursor protein is cleaved on the plasma membrane by a membrane-bound endoprotease and that the specificity of peptide bond hydrolysis is largely independent of the primary sequence of the precursor. The principal determinants of cleavage appear to be an alpha-helical conformation and the distance (12-13 residues) of the hydrolyzed bond from membrane.
Sisodia
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Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D010450:Endopeptidases