title: Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1.
abstract: Presenilin 1 (PS1) comprises a catalytic subunit of γ-secretase, which is an intramembrane-cleaving protease responsible for generation of amyloid-β peptides as well as Notch cleavage, the latter being implicated in cancer. We have shown that transmembrane domains (TMDs) 1, 6, 7, and 9 of PS1 form the "catalytic pore" structure within the membrane for intramembrane proteolysis. Here we report a novel monoclonal antibody 9D11, which directly recognizes the TMD1-proximal residues in the hydrophilic loop region. Intriguingly, 9D11 inhibited the γ-secretase activity irrespective of the binding of known γ-secretase inhibitors and abolished Notch signaling-dependent cancer cell viability. Our data suggest that the juxtamembrane region of TMD1 of PS1 is a novel molecular target for the mechanism-based inhibition of γ-secretase and the development of the anticancer drug.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takagi-Niidome
authors.forename: Satoko
authors.initials: S
authors.lastname: Osawa
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D020134:Catalytic Domain; D002460:Cell Line; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053764:Presenilin-1 / Q000737:chemistry / Q000276:immunology*; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D000911:Antibodies, Monoclonal; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases