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: 6.34). 05/2006; 26(14):3821-8. DOI: 10.1523/JNEUROSCI.5354-05.2006
Source: PubMed


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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    ABSTRACT: Read the full article 'Important functional role of residue x of the presenilin GxGD protease active site motif for APP substrate cleavage specificity and substrate selectivity of γ-secretase' on doi: 10.1111/jnc.12124.
    Full-text · Article · Apr 2013 · Journal of Neurochemistry
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    • "The role of AICD in neurodegeneration is controversial. The lifetime of AICD is short [64], [65] (but tagged versions have a longer lifetime [66], [67], [68]) impeding efforts to identify which cellular pathways it participates in. In spite of this, it has been shown that AICD does activate gene transcription but there are many targets that vary depending on the cell line and strategy used in the investigation (reviewed in [12], [22], [69]). "
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    ABSTRACT: The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58) enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.
    Preview · Article · Sep 2012 · PLoS ONE
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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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    ABSTRACT: Recent intriguing evidence suggests that metabolites of amyloid precursor protein (APP), mutated in familial forms of Alzheimer's disease (AD), play critical roles in developmental and postnatal neurogenesis. Of note is soluble APPα (sAPPα) that regulates neural progenitor cell proliferation. The APP family encompasses a group of ubiquitously expressed and evolutionarily conserved, type I transmembrane glycoproteins, whose functions have yet to be fully elucidated. APP can undergo proteolytic cleavage by mutually exclusive pathways. The subtle structural differences between metabolites generated in the different pathways, as well as their equilibrium, may be crucial for neuronal function. The implications of this new body of evidence are significant. Miscleavage of APP would readily impact developmental and postnatal neurogenesis, which might contribute to cognitive deficits characterizing Alzheimer's disease. This review will discuss the implications of the role of the APP family in neurogenesis for neuronal development, cognitive function, and brain disorders that compromise learning and memory, such as AD.
    Full-text · Article · Jun 2012 · Frontiers in Neuroscience
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