title: Development of CBAP-BPyne, a probe for γ-secretase and presenilinase.
abstract: γ-Secretase undergoes endoproteolysis of its catalytic subunit, presenilin (PS), to form PS N-terminal and C-terminal fragments (PS1-NTF/CTF), which generate the active site. PS endoproteolysis, catalyzed by presenilinase (PSase), remains poorly understood and requires novel chemical approaches for its mechanistic study. CBAP is a dual inhibitor that suppresses both γ-secretase and PSase activities. To probe γ-secretase and PSase activity in cells, we have synthesized the clickable photoaffinity probe CBAP-BPyne. We found that CBAP-BPyne specifically labels PS1-NTF and signal peptide peptidase (SPP). CBAP-BPyne is a valuable tool to directly study the mechanism of endoproteolysis.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA ; Biochemistry and Molecular Biology Program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Natalya
authors.initials: N
authors.lastname: Gertsik
authors.affiliation: Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry and Chemical Biology, Cambridge, MA 02139, USA ; Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Groton, CT 06340, USA.
authors.forename: T Eric
authors.initials: TE
authors.lastname: Ballard
authors.affiliation: Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Groton, CT 06340, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Am Ende
authors.affiliation: Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry and Chemical Biology, Cambridge, MA 02139, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Johnson
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li