The protease inhibitory properties of the Alzheimer's beta-amyloid precursor protein.
We have expressed the 57-amino acid Kunitz domain of the Alzheimer's beta-amyloid precursor protein (APP751) as a bacterial fusion protein. The protease inhibitory properties of the purified fusion protein, BX9, were virtually identical in all respects tested to those of purified secreted APP751. Both proteins strongly inhibited pancreatic trypsin (Kis = 0.2 and 0.3 nM) and less well epidermal growth factor-binding protein (Kis = 1 and 3.5 nM), alpha-chymotrypsin (Kis = 3 and 6 nM), and the gamma-subunit of nerve growth factor (Kis = 8 and 9 M). Neither protein appreciably inhibited plasma and pancreatic kallikreins, thrombin, lung tryptase, neutrophil elastase, or cathepsin G. The remarkable similarity of the protease inhibitory profile of BX9 to that of secreted APP751 suggests that proper intramolecular disulfide bond formation has occurred in the bacterial fusion protein and leads to the conclusion that the amyloid precursor protein Kunitz domain is a relatively specific inhibitor of only a few trypsin-like arginine esterases.
Sinha
S
S
Athena Neurosciences, Inc., South San Francisco, California 94080.
Dovey
H F
HF
Seubert
P
P
Ward
P J
PJ
Blacher
R W
RW
Blaber
M
M
Bradshaw
R A
RA
Arici
M
M
Mobley
W C
WC
Lieberburg
I
I
D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors; D011498:Protein Precursors / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D014361:Trypsin Inhibitors
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D009414:Nerve Growth Factors; D011480:Protease Inhibitors; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D014361:Trypsin Inhibitors; D010450:Endopeptidases; D002918:Chymotrypsin