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-Amyloid Precursor Protein
-SECRETASE CLEAVAGE
(Received for publication, March 5, 1996, and in revised form, May 8, 1996)
From Scios Inc., Mountain View, California 94043
The formation of 
-amyloid by processing of its
precursor protein is a characteristic of Alzheimer's disease. Two
proteolytic cleavages produce the amino and carboxyl termini of
-amyloid, with the latter cleavage site located within the
transmembrane domain. Using DNA mutagenesis, we investigated the
membrane position and sequence requirements for carboxyl-terminal
processing of the -amyloid domain. Substitution of negatively
charged residues across positions 40-46 of the -amyloid domain
precluded both -amyloid formation and precursor maturation
associated with secretory protein transport. In contrast, identical
substitutions from positions 48-50 had no adverse effects. Since
charged residues typically prevent protein membrane insertion, these
data define the membrane boundary to position 46/47, a location
allowing greater access to carboxyl-terminal processing of -amyloid,
possibly without membrane destruction. Deletions within the
carboxyl-terminal domain, including 4 residues spanning positions
39-42 of -amyloid, resulted in formation of the -amyloid
peptide. Substituting residues 38-47 or 39-56 of the -amyloid
domain in the precursor with a transmembrane sequence from another
protein yielded a ~4-kDa -amyloid peptide, reflecting a loose
residue specificity for carboxyl-terminal processing to
-amyloid.
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