| Autor: |
Castro, Maria, Marks, Cara Berman, Nilsson, Björn, Anderson, Stephen |
| Zdroj: |
FEBS Letters; January 1990, Vol. 267 Issue: 2 p207-212, 6p |
| Abstrakt: |
Alternative splicing of the Alzheimer's amyloid β protein precursor (ABPP) message leads to the production of several variants of this precursor polypeptide. Two of these variants contain a domain that is highly homologous to members of the Kunitz class of protease inhibitors. In order to initiate a study of the physiological role of this domain, we have produced active ABPP Kunitz inhibitor by constructing and expressing a synthetic gene in E. coli. Nerve growth factor (NGF) deficiency has been suggested as a possible cause of the neural degeneration characteristic of Alzheimer's disease, and trypsin and γ-NGF are the two enzymes that have been shown to be capable of processing β-NGF precursor to active, mature β-NGF in vitro, therefore the specificity of purified recombinant ABPP Kunitz inhibitor was analyzed with respect to these two proteases. Binding of isolated ABPP Kunitz domain both to trypsin ( Ki,app< 10 nM and to γ-NGF ( Ki,app= 300 nM) was observed. This difference in binding to the two proteases correlates with the approximately 20-fold higher rate observed for in vitro processing of the β-NGF precursor by trypsin compared to processing by γ-NGF, indicating that perhaps the inhibitor mimics the interaction of the β-NGF precursor with proteases. The kallikrein actually responsible for β-NGF precursor processing in vivo is unknown, but these results suggest that it is capable of being significantly inhibited by exposure to the ABPP Kunitz domain. |
| Databáze: |
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