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Solenne Ousson, Arman Saric, Aurelie Baguet, Christophe Losberger, Stephane Genoud, Francis Vilbois, Bruno Permanne, Ishrut Hussain and Dirk Beher Substrate determinants in the C99 juxtamembrane domains differentially affect γ–secretase cleavage specificity and modulator pharmacology Journal of Neurochemistry 125

Article first published online: 18 JAN 2013 | DOI: 10.1111/jnc.12129

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Mutagenesis studies were conducted to explore γ-secretase cleavage specificity and modulation. Elongation of the distal juxtamembrane domain changes cleavage specificity. The K28E mutation at the proximal juxtamembrane domain changes γ-secretase cleavage specificity and modulator pharmacology. Thus, we have identified critical determinants in the proximal and distal juxtamembrane domains of the APP C99 substrate which differentially affect γ-secretase cleavage specificity and modulator pharmacology. Modulation of substrate binding could be a potential mechanism of action for γ-secretase modulators.

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