K. Boland et al., SPECIFICITY IN RECOGNITION OF AMYLOID-BETA PEPTIDE BY THE SERPIN-ENZYME COMPLEX RECEPTOR IN HEPATOMA-CELLS AND NEURONAL CELLS, The Journal of biological chemistry, 270(47), 1995, pp. 28022-28028
The serpin-enzyme complex (SEC) receptor was originally identified usi
ng a synthetic peptide (peptide 105Y) based on the sequence of a candi
date receptor-binding domain of alpha 1-antitrypsin (1-AT) and was sub
sequently shown to be a receptor on the surface of hepatocytes, monocy
tes, and neutrophils for recognition of alpha 1-AT-elastase and severa
l other serpin-enzyme complexes (Perlmutter, D. H., Glover, G. I., Riv
etna, M., Schasteen, C. S., and Fallen, R. J. (1990) Proc. Natl. Acad.
Sci. U.S.A. 87, 3753-3757). Studies of the minimal requirements for b
inding to SEC receptor (SEC-R) showed that a pentapeptide FVFLM within
the carboxyl-terminal tail of alpha 1-AT was sufficient for binding t
o SEC-R and interacted with SEC-R in a sequence-specific manner (Josli
n, G., Krause, J. E., Hershey, A. D,, Adams, S. P., Fallen, R. J., and
Perlmutter, D. H. (1991) J. Biol. Chem. 266, 21897-21902). Sequence m
otifs bearing homology with this pentapeptide domain were found in the
amyloid-beta peptide, and amyloid-beta peptide 1-42 was shown to comp
ete for binding to SEC-R on hepatoma cells (Joslin, G., Fallen, R. J.,
Bullock, J., Adams, S. P., and Perlmutter, D. H. (1991) J. Biol. Chem
. 266, 11281-11288). In this study we examined the sequence specificit
y by which amyloid-beta peptide competes for binding to SEC-R and exam
ined the possibility that SEC-R is expressed in cells of neuronal orig
in. The results show that amyloid-beta-(25-35) and amyloid-beta-(31-35
) compete for binding to SEC-R as effectively as amyloid-beta-(1-39),
amyloid-beta-(1-40), and amyloid-beta-(1-42). Amyloid-beta-(1-16) does
not compete for binding to SEC-R. There is cross-competition for bind
ing to the same site by I-125-peptide 105Y and amyloid-beta-(25-35) as
well as by I-125-Y amyloid-beta-(25-35) and peptide 105Y. By deletion
s and substitutions within amyloid-beta-(25-35) and generation of chim
eric amyloid-beta-alpha 1-AT peptides, amyloid-beta-(31-35) is shown t
o be critical for binding to the SEC receptor. However, the upstream r
egion, amyloid-beta-(25-30), also contributes to recognition by SEC-R.
The SEC-R is present on the surface of a neuronal cell line PC12 as w
ell as that of murine cortical neurons in primary culture, and the spe
cificity of neuronal SEC-R for amyloid-beta peptide is identical to th
at on hepatoma cells. Finally, SEC-R mediates internalization and degr
adation of amyloid beta-peptide in PC12 cells. These results provide e
vidence that SEC-R plays a role in metabolism of amyloid-beta peptide
in the nervous system.