Article

The GxGD motif of presenilin contributes to catalytic function and substrate identification of γ-secretase

University of Freiburg, Freiburg, Baden-Württemberg, Germany
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 05/2006; 26(14):3821-8. DOI: 10.1523/JNEUROSCI.5354-05.2006
Source: PubMed

ABSTRACT Gamma-secretase is a multisubunit aspartyl protease complex that catalyzes intramembrane cleavage of beta-amyloid precursor protein (APP), a substrate key to Alzheimer's disease pathogenesis, and of Notch, a substrate crucial for cell differentiation. How gamma-secretase recognizes and selects substrates is currently barely understood. Recent data suggest that its subunit nicastrin serves as an initial substrate receptor, which might subsequently forward substrates to the active site domain located in its catalytic subunit presenilin (PS), where an additional substrate binding site has been proposed. We now used an active site domain swapping approach of PS1 with its most distant homolog, spermatogenesis defective (SPE-4), to identify sequence determinants in this region. Strikingly, when the active site domain of PS1 was exchanged with that of SPE-4, the chimeric protein, PS1/SPE-4(6/7), supported APP but not Notch processing. In addition, PS1/SPE-4(6/7) was strongly impaired in Caenorhabditis elegans Notch signaling in vivo. Mapping experiments identified a single amino acid at position x of the GxGD motif, which contains one of the two active site aspartates, to be responsible for the observed defect in Notch processing and signaling. Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of gamma-secretase.

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    • "In fact, substitution of the PSEN-Gly384 with Ala (G384A) results in an aggressive PSEN FAD linked mutation (Cruts et al. 1995). In addition to their crucial roles in the catalytic mechanism, both the PSEN-Gly382 and PSEN-Gly384 residues have been implicated in substrate selectivity (Yamasaki et al. 2006). Clearly, mutagenesis studies on the highly conserved residues of the GXGD presenilin motif have provided significant mechanistical insights into the function of the c-secretase. "
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    • "Subsequent RIP by γ secretase releases the APP intracellular domain (AICD) that can translocate to the nucleus and a P3 peptide (Haass and Selkoe, 1993; Yu et al., 2000; Kimberly et al., 2001; Francis et al., 2002). PS are the catalytic core of the aspartyl protease γ-secretase complex (Wolfe et al., 1999; Yamasaki et al., 2006). In the amyloidogenic cleavage pathway, APP is first cleaved by β-secretase to produce sAPPβ and a βAPP-CTF. "
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