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Activated Notch1 associates with a presenilin‐1/γ‐secretase docking site
Author(s) -
Ramdya Pavan,
Skoch Jesse,
Bacskai Brian J.,
Hyman Bradley T.,
Berezovska Oksana
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02030.x
Subject(s) - presenilin , förster resonance energy transfer , docking (animal) , ligand (biochemistry) , chemistry , gamma secretase , binding site , notch signaling pathway , microbiology and biotechnology , signal transduction , biophysics , receptor , biochemistry , fluorescence , biology , alzheimer's disease , medicine , physics , nursing , disease , pathology , quantum mechanics
Presenilin‐1 (PS1), implicated as the active component of the γ‐secretase enzymatic complex, is known to cleave the cell surface receptor Notch1 after ligand binding. Here we directly visualize Notch1–PS1 interactions using a novel fluorescence lifetime imaging microscopy assay to monitor fluorescence resonance energy transfer. We demonstrate that endogenous Notch1 and PS1 move into close proximity at the cell surface after activation of Notch1 by the Delta1 ligand. A constitutively active N‐terminally truncated form of Notch1, an immediate substrate of the γ‐secretase complex, similarly is found in close proximity to PS1. Interestingly, this interaction remains in the presence of a potent γ‐secretase active site inhibitor. Thus ligand binding to Notch1 appears to result in access of truncated Notch1 to a putative docking site on the PS1–γ‐secretase complex. These results suggest a novel mechanism of ligand binding‐mediated signal transduction of Notch1.