title: γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase.
abstract: γ-Secretase inhibitors (GSIs) and modulators (GSMs) are at the frontline of cancer and Alzheimer's disease research, respectively. While both are therapeutically promising, not much is known about their interactions with proteins other than γ-secretase. Signal peptide peptidase (SPP), like γ-secretase, is a multispan transmembrane aspartyl protease that catalyzes regulated intramembrane proteolysis. We used active site-directed photophore walking probes to study the effects of different GSIs and GSMs on the active sites of γ-secretase and SPP and found that nontransition state GSIs inhibit labeling of γ-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of GSMs, which have little effect on the labeling of γ-secretase but diminish labeling of SPP. These results demonstrate that GSIs and GSMs are altering the structure of not only γ-secretase but also SPP, leading to potential changes in enzyme activity and specificity that may impact the clinical outcomes of these molecules.
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Natalya
authors.initials: N
authors.lastname: Gertsik
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.|∥Clinical Genetics Unit Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia.
authors.forename: De-Ming
authors.initials: DM
authors.lastname: Chau
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001577:Benzophenones; D054852:Small Molecule Libraries; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase