Specificity in recognition of amyloid-β peptide by the serpin-enzyme complex receptor in hepatoma cells and neuronal cells

K. Boland, K. Manias, D. H. Perlmutter

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Abstract

The serpin-enzyme complex (SEC) receptor was originally identified using a synthetic peptide (peptide 105Y) based on the sequence of a candidate receptor-binding domain of α1-antitrypsin (1-AT) and was subsequently shown to be a receptor on the surface of hepatocytes, monocytes, and neutrophils for recognition of α1-AT-elastase and several other serpin-enzyme complexes (Perlmutter, D. H., Glover, G. I., Rivetna, M., Schasteen, C. S., and Fallon, R. J. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 3753-3757). Studies of the minimal requirements for binding to SEC receptor (SEC-R) showed that a pentapeptide FVFLM within the carboxyl-terminal tail of α1-AT was sufficient for binding to SEC-R and interacted with SEC-R in a sequence-specific manner (Joslin, G., Krause, J. E., Hershey, A.D., Adams, S. P., Fallon, R. J., and Perlmutter, D. H. (1991) J. Biol. Chem. 266, 21897-21902). Sequence motifs bearing homology with this pentapeptide domain were found in the amyloid-β peptide, and amyloid-β peptide 1-42 was shown to compete for binding to SEC- R on hepatoma cells (Joslin, G., Fallon, 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 specificity by which amyloid-β peptide competes for binding to SEC-R and examined the possibility that SEC-R is expressed in cells of neuronal origin. The results show that amyloid-β-(25-35) and amyloid-β-(31-35) compete for binding to SEC-R as effectively as amyloid- β-(1-39), amyloid-β-(140), and amyloid-β(1-42). Amyloid-β-(1-16) does not compete for binding to SEC-R. There is cross-competition for binding to the same site by 125I-peptide 105Y and amyloid-β-(25-35) as well as by 125I-Y amyloid-β-(25-35) and peptide 105Y. By deletions and substitutions within amyloid-β-(25-35) and generation of chimeric amyloid-β-α1-AT peptides, amyloid-β-(31-35) is shown to be critical for binding to the SEC receptor. However, the upstream region, amyloid-β-(25-30), also contributes to recognition by SEC-R. The SEC-R is present on the surface of a neuronal cell line PC12 as well as that of murine cortical neurons in primary culture, and the specificity of neuronal SEC-R for amyloid-β peptide is identical to that on hepatoma cells. Finally, SEC-R mediates internalization and degradation of amyloid β-peptide in PC12 cells. These results provide evidence that SEC-R plays a role in metabolism of amyloid-β peptide in the nervous system.

Original languageEnglish
Pages (from-to)28022-28028
Number of pages7
JournalJournal of Biological Chemistry
Volume270
Issue number47
DOIs
StatePublished - 1995

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