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

Iben, Lawrence G.; Olson, R. E.; Balanda, Lynn A.; Jayachandra, Sukhanya; Robertson, Barbara; Hay, Vanessa; Corradi, John P.; Prasad, C. V. C.; Zaczek, Robert; Albright, Charles F.; Toyn, Jeremy H.

doi:10.1074/jbc.m707002200

Cited by 23 publications

(23 citation statements)

References 47 publications

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“…Nevertheless, the reduced function of similar mutants in SPP and PS clearly suggests biochemical similarities of both types of GXGD-type proteases. Such similarities, which are probably related to structural homologies, are supported by the finding that certain ␥-secretase inhibitors such as L-685,458 and helical peptides mimicking the substrate-docking site block SPP activity as well (15,24,25,38,39). Interestingly, whereas L-685,458 significantly reduced SPP activity, N-(N-(3,5-difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester (DAPT) failed to do so (38).…”

Section: Comparison Of the Biochemical And Cellular Properties Of Gxgmentioning

confidence: 51%

Intramembrane Proteolysis by Signal Peptide Peptidases: A Comparative Discussion of GXGD-type Aspartyl Proteases

Fluhrer

Steiner

Haass

2009

Journal of Biological Chemistry

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Intramembrane-cleaving proteases are required for reverse signaling and membrane protein degradation. A major class of these proteases is represented by the GXGD-type aspartyl proteases. GXGD describes a novel signature sequence that distinguishes these proteases from conventional aspartyl proteases. Members of the family of the GXGD-type aspartyl proteases are the Alzheimer disease-related ␥-secretase, the signal peptide peptidases and their homologs, and the bacterial type IV prepilin peptidases. We will describe the major biochemical and functional properties of the signal peptide peptidases and their relatives. We then compare these properties with those of ␥-secretase and discuss common mechanisms but also point out a number of substantial differences.

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Section: Comparison Of the Biochemical And Cellular Properties Of Gxgmentioning

confidence: 51%

Intramembrane Proteolysis by Signal Peptide Peptidases: A Comparative Discussion of GXGD-type Aspartyl Proteases

Fluhrer

Steiner

Haass

2009

Journal of Biological Chemistry

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“…These are analogous to the cleavage events in the APP TMD that generate the Aβpeptides suggesting that proteolytic processing of at least APP and Notch is affected in a similar manner, thereby questioning the specificity of GSMs for APP. (iii) The aspartyl intramembrane-cleaving protease signal peptide peptidase (SPP) has been demonstrated to harbor a binding site for NSAID-type GSMs [29], [30]. SPP is homologous to PSEN but functions as a homodimer without accessory proteins, and γ-secretase and SPP substrates do not show any overlap.…”

Section: Discussionmentioning

confidence: 99%

Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

et al. 2012

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The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex.

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“…In contrast, there was no significant difference in the IC 50 values for DAPT under the same conditions that were 8.6 and 7.9 M, respectively. A possible explanation for the IC 50 shift for L-685,458 would be the presence of abundant quantities of signal peptide peptidases in the cell-free extracts that bind with high affinity to L-685,458 but with low affinity to DAPT (32). Under the conditions used at the E/S ratio of 1:1, L-685,458 at concentrations in the low nanomolar range would be mostly titrated by signal peptide peptidases (32) and so unavailable to inhibit ␥-secretase.…”

Section: Resultsmentioning

confidence: 99%

The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression

Burton

Meredith

Barten

et al. 2008

Journal of Biological Chemistry

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119

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The amyloid-␤ (A␤) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-␤ precursor protein (APP) through consecutive proteolytic cleavages by ␤-site APP-cleaving enzyme and ␥-secretase. Unexpectedly ␥-secretase inhibitors can increase the secretion of A␤ peptides under some circumstances. This "A␤ rise" phenomenon, the same inhibitor causing an increase in A␤ at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the A␤ rise depends on the ␤-secretase-derived C-terminal fragment of APP (␤CTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of A␤, known as "p3," formed by ␣-secretase cleavage, did not exhibit a rise. In addition to the A␤ rise, low ␤CTF or C99 expression decreased ␥-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, ␥-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of A␤ under conditions of low substrate expression. The A␤ rise was also observed in rat brain after dosing with the ␥-secretase inhibitor BMS-299897. The A␤ rise and potency shift are therefore relevant factors in the development of ␥-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the A␤ rise, including the "incomplete processing" and endocytic models, are discussed.Evidence suggests that the amyloid-␤ (A␤) 9 peptide plays a key role in Alzheimer disease. A␤ is generated by proteolytic processing of the amyloid-␤ precursor protein (APP) through consecutive cleavages by the ␤-site APP-cleaving enzyme (BACE) and ␥-secretase. APP is cleaved by BACE to form a ␤-secretase-derived C-terminal fragment of APP (␤CTF), which undergoes further cleavage by ␥-secretase to form A␤. In addition, APP is cleaved by ␣-secretase to form ␣CTF, which undergoes ␥-secretase cleavage to produce an N-terminally truncated form of A␤ known as "p3." Using the conventional amino acid numbering of A␤, BACE cleavage leads to A␤ peptides with N-terminal ends at positions 1 and 11, whereas ␣-secretase leads to p3 peptides with an N-terminal end at position 17. Cleavage of ␤CTF and ␣CTF by ␥-secretase produces a mixture of different C termini in the resulting A␤ and p3 peptides. For example, the predominant ␥-secretase cleavage of ␤CTFs at position 40 produces A␤-(1-40) and A␤-(11-40), whereas other ␥-secretase cleavage sites produce a range of less abundant A␤ peptides, such as the disease-associated A␤-(1-42) (1, 2).

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

Cited by 23 publications

References 47 publications

Intramembrane Proteolysis by Signal Peptide Peptidases: A Comparative Discussion of GXGD-type Aspartyl Proteases

Intramembrane Proteolysis by Signal Peptide Peptidases: A Comparative Discussion of GXGD-type Aspartyl Proteases

Presenilin Is the Molecular Target of Acidic γ-Secretase Modulators in Living Cells

The Amyloid-β Rise and γ-Secretase Inhibitor Potency Depend on the Level of Substrate Expression

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