Nicastrin Functions as a γ-Secretase-Substrate Receptor

Shah, Sanjiv; Lee, Sheu Fen; Tabuchi, Katsuhiko; Hao, Yi; Yu, Cong; LaPlant, Quincey; Ball, Haydn L.; Dann, Charles E.; Südhof, Thomas C.; Yu, Gang

doi:10.1016/j.cell.2005.05.022

Cited by 426 publications

(466 citation statements)

References 32 publications

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“…It has recently been shown that the extracellular domain of nicastrin is involved in the substrate recognition, whereas the transmembrane domain of the protein is critical in the assembly and trafficking of the γ-secretase complex to the cell surface [4,43]. The significance of this protein is further highlighted by RNAi and gene knock out studies, which clearly demonstrated that nicastrin is essential for the assembly of PS1/γ-secretase complex and secretion of Aβ peptide [20,30,31,54,56].…”

Section: Discussionmentioning

confidence: 99%

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Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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Section: Discussionmentioning

confidence: 99%

“…Ectodomain shedding is a prerequisite for γ-secretase cleavage of substrates [47]. The extracellular domain of nicastrin binds to C-terminal stubs generated by ectodomain shedding of type I membrane protein substrates, thus recruiting substrates for cleavage by the γ-secretase [43].…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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“…In contrast to presenilin, which requires additional subunits for enzyme activity, the active SPP enzyme does not require additional subunits for activity (32). This implies that the additional subunits of ␥-secretase, which are essential for enzyme maturation, contribute only to non-catalytic functions, such as the recognition and binding of substrates by nicastrin (35,36). SPP therefore represents a simplified model for ␥-secretase.…”

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confidence: 99%

Signal Peptide Peptidase and γ-Secretase Share Equivalent Inhibitor Binding Pharmacology

Iben¹,

Olson²,

Balanda

et al. 2007

Journal of Biological Chemistry

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The enzyme ␥-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of ␥-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and ␥-secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid ␤-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, ␥-secretase inhibitor radioligands were used to evaluate SPP and ␥-secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for ␥-secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of ␥-secretase binding sites, making it essential to use selective radioligands for evaluation of ␥-secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.

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“…S2 cleavage occurs just external to the transmembrane domain and is catalyzed by ADAM-type metalloproteases (8,29). This creates a short-lived intermediate, N TM *, which appears to be recognized through its amino terminus by nicastrin (44), a component of a multiprotein enzyme complex called ␥-secretase. N TM * is then cleaved by ␥-secretase at several sites within the transmembrane domain (10,19,42).…”

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confidence: 99%

Leukemia-Associated Mutations within the NOTCH1 Heterodimerization Domain Fall into at Least Two Distinct Mechanistic Classes

Malecki

Sanchez-Irizarry

Mitchell

et al. 2006

Molecular and Cellular Biology

251

281

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The NOTCH1 receptor is cleaved within its extracellular domain by furin during its maturation, yielding two subunits that are held together noncovalently by a juxtamembrane heterodimerization (HD) domain. Normal NOTCH1 signaling is initiated by the binding of ligand to the extracellular subunit, which renders the transmembrane subunit susceptible to two successive cleavages within and C terminal to the heterodimerization domain, catalyzed by metalloproteases and ␥-secretase, respectively. Because mutations in the heterodimerization domain of NOTCH1 occur frequently in human T-cell acute lymphoblastic leukemia (T-ALL), we assessed the effect of 16 putative tumor-associated mutations on Notch1 signaling and HD domain stability. We show here that 15 of the 16 mutations activate canonical NOTCH1 signaling. Increases in signaling occur in a ligand-independent fashion, require ␥-secretase activity, and correlate with an increased susceptibility to cleavage by metalloproteases. The activating mutations cause soluble NOTCH1 heterodimers to dissociate more readily, either under native conditions (n ‫؍‬ 3) or in the presence of urea (n ‫؍‬ 11). One mutation, an insertion of 14 residues immediately N terminal to the metalloprotease cleavage site, increases metalloprotease sensitivity more than all others, despite a negligible effect on heterodimer stability by comparison, suggesting that the insertion may expose the S2 site by repositioning it relative to protective NOTCH1 ectodomain residues. Together, these studies show that leukemia-associated HD domain mutations render NOTCH1 sensitive to ligand-independent proteolytic activation through two distinct mechanisms.The development of multicellular organisms is orchestrated by a limited number of highly conserved signaling pathways. One such pathway involves NOTCH receptors and downstream mediators, which can variously regulate the specification of cell fate, proliferation, self-renewal, survival, and apoptosis in a dose-and context-dependent fashion (3,47).Like other members of the NOTCH receptor family, mammalian NOTCH1 is a large multimodular type I transmembrane glycoprotein (Fig. 1A). During maturation, NOTCH1 undergoes proteolytic processing by furin at a site termed S1 that lies ϳ70 amino acids external to the transmembrane domain (25), yielding two noncovalently associated extracellular (N EC ) and transmembrane (N TM ) subunits (6,25,37). N EC contains 36 N-terminal epidermal growth factor (EGF)-like repeats that participate in binding to ligands (23, 39, 51) and three iterated LIN-12/NOTCH repeats (LNR), which help to maintain NOTCH receptors in the "off" state prior to ligand binding (13,24,40). The association of N EC and N TM is mediated by sequences lying immediately N terminal (HD-N) and C terminal (HD-C) of site S1; together, these sequences constitute the NOTCH subunit association, or "heterodimerization" (HD) domain (40).Binding of ligands to N EC triggers two sequential proteolytic events within the N TM subunit at sites S2 and S3. S2 cleavage occurs just...

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Nicastrin Functions as a γ-Secretase-Substrate Receptor

Cited by 426 publications

References 32 publications

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Signal Peptide Peptidase and γ-Secretase Share Equivalent Inhibitor Binding Pharmacology

Leukemia-Associated Mutations within the NOTCH1 Heterodimerization Domain Fall into at Least Two Distinct Mechanistic Classes

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