Signal Peptide Peptidase and γ-Secretase Share Equivalent Inhibitor Binding Pharmacology

The enzyme γ-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of γ-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and γ-secretase are...

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Veröffentlicht in:The Journal of biological chemistry 2007-12, Vol.282 (51), p.36829
Hauptverfasser: Lawrence G. Iben, Richard E. Olson, Lynn A. Balanda, Sukhanya Jayachandra, Barbara J. Robertson, Vanessa Hay, John Corradi, C. V. C. Prasad, Robert Zaczek, Charles F. Albright, Jeremy H. Toyn
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Sprache:eng
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Zusammenfassung:The enzyme γ-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of γ-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and γ-secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid β-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, γ-secretase inhibitor radioligands were used to evaluate SPP and γ-secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for γ-secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of γ-secretase binding sites, making it essential to use selective radioligands for evaluation of γ-secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M707002200