Supplemental Data Nicastrin Functions as a γ-Secretase-Substrate Receptor

Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cell (Impact Factor: 32.24). 09/2005; 122(3):435-47. DOI: 10.1016/j.cell.2005.05.022
Source: PubMed


gamma-secretase catalyzes the intramembrane cleavage of amyloid precursor protein (APP) and Notch after their extracellular domains are shed by site-specific proteolysis. Nicastrin is an essential glycoprotein component of the gamma-secretase complex but has no known function. We now show that the ectodomain of nicastrin binds the new amino terminus that is generated upon proteolysis of the extracellular APP and Notch domains, thereby recruiting the APP and Notch substrates into the gamma-secretase complex. Chemical- or antibody-mediated blocking of the free amino terminus, addition of purified nicastrin ectodomain, or mutations in the ectodomain markedly reduce the binding and cleavage of substrate by gamma-secretase. These results indicate that nicastrin is a receptor for the amino-terminal stubs that are generated by ectodomain shedding of type I transmembrane proteins. Our data are consistent with a model where nicastrin presents these substrates to gamma-secretase and thereby facilitates their cleavage via intramembrane proteolysis.

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    • "Nicastrin is a type I transmembrane glycoprotein considered to be the scaffolding protein within the γ-secretase complex. Nicastrin may also act as the γ-secretase receptor [144]. The seven-transmembrane APH-1 interacts with nicastrin to form a stable intermediate in an early assembly stage of the γ-secretase complex [140,141], whereas the two-pass transmembrane component PEN2 regulates PS endoproteolysis [145,146]. "
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    ABSTRACT: The beta-amyloid (Abeta) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer's disease (AD). Abeta is produced through sequential cleavage of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Abeta generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.
    Molecular Neurodegeneration 01/2014; 9(1):6. DOI:10.1186/1750-1326-9-6 · 6.56 Impact Factor
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    • "Such a two-step process has been observed for other substrates of γ-secretase including L1 [26], protein-tyrosine kinase 7 (PTK7) [55] and the epidermal growth factor-like betacellulin precursor [56]. This sequential processing appears to be a general mechanism for γ-secretase substrates with permissive cytoplasmic and transmembrane domains [57], allowing for nicastrin, a member of the γ-secretase complex, to recognize RIP substrates [58]. "
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    PLoS ONE 08/2013; 8(8):e73296. DOI:10.1371/journal.pone.0073296 · 3.23 Impact Factor
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    • "Mutations on either aspartate abolish the enzymatic activity of γ-secretase complex [60]. With a large highly glycosylated ectodomain, nicastrin has been implicated to function as the initial recognition of substrates [77]. Electronic microscopic analysis and single particle imaging revealed the existence of intramembrane water-accessible cylindrical chamber in gamma-secretase with a low-density cavity from extracellular side [78,79]. "
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