Abstract
Mutations in the presenilins cause Alzheimer’s disease (AD) and alter γ-secretase activity to increase the production of the 42-residue amyloid-β peptide (Aβ) found disproportionally in the cerebral plaques that characterize the disease. The serpentine presenilins are required for transmembrane cleavage of both the amyloid-β precursor protein (APP) and the Notch receptor by γ-secretase, and presenilins are biochemically associated with the protease. Inhibitors of γ-secretase have provided critical clues to the function of presenilins. Pharmacological profiling suggested that γ-secretase is an aspartyl protease, leading to the identification of two conserved aspartates important to presenilin’s role in proteolysis. Conversion of transition-state analogue inhibitors of γ-secretase to affinity reagents resulted in specific tagging of the heterodimeric form of presenilins, strongly suggesting that the active site of γ-secretase lies at the interface of the presenilin heterodimer. Heterodimeric presenilin appears to be the catalytic portion of a multi-protein γ-secretase complex.
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Wolfe, M.S. γ-Secretase inhibitors as molecular probes of presenilin function. J Mol Neurosci 17, 199–204 (2001). https://doi.org/10.1385/JMN:17:2:199
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DOI: https://doi.org/10.1385/JMN:17:2:199