Identity and function of γ‐secretase

Kimberly, W. Taylor; Wolfe, Michael S.

doi:10.1002/jnr.10736

Cited by 89 publications

(46 citation statements)

References 74 publications

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“…6, our data strongly suggest the possibility that under normal conditions, after ␤-or ␣-cleavage of APP, the resulting CTF␤ and CTF␣ first undergo ⑀-cleavage, followed by a sequential but rapid -cleavage, and then by a ␥-cleavage, commencing at the site closest to the membrane boundary and proceeding toward the site in the middle of the transmembrane domain of APP. Support for this sequential action model also comes from the notion that water molecules play an important role in the peptide bond hydrolysis catalyzed by a protease, and ␥-secretase has been proposed to be an aspartyl protease (4). According to the catalytic mechanism of aspartyl protease, in order to hydrolyze the peptide bond of the substrate, one of the two aspartate residues in the enzyme active site, disposed on opposite faces of the peptide bond to be cleaved, needs to first act as general base to activate the water molecule.…”

Section: Discussionmentioning

confidence: 99%

“…␤-Secretase has been identified as a type I membrane aspartyl protease (2,3). Although the exact nature of ␥-secretase is still a matter of debate, accumulating evidence supports the idea that ␥-secretase is a multiple molecular complex composed of, at least, presenilins, nicastrin, Aph-1, and Pen-2 and that presenilin may function as the catalytic subunit (4).…”

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confidence: 99%

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γ-Cleavage Is Dependent on ζ-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain

Zhao

Cui

Mao

et al. 2005

Journal of Biological Chemistry

127

163

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␤-Amyloid precursor protein apparently undergoes at least three major cleavages, ␥-, ⑀-, and the newly identified -cleavage, within its transmembrane domain to produce secreted ␤-amyloid protein (A␤). However, the roles of ⑀-and -cleavages in the formation of secreted A␤ and the relationship among these three cleavages, namely ⑀-, -, and ␥-cleavages, remain elusive. We investigated these issues by attempting to determine the formation and turnover of the intermediate products generated by these cleavages, in the presence or absence of known ␥-secretase inhibitors. By using a differential inhibition strategy, our data demonstrate that A␤ 46 is an intermediate precursor of secreted A␤. Our co-immunoprecipitation data also reveal that, as an intermediate, A␤ 46 is tightly associated with presenilin in intact cells. Furthermore, we identified a long A␤ species that is most likely the long sought after intermediate product, A␤ 49 , generated by ⑀-cleavage, and this A␤ 49 is further processed by -and ␥-cleavages to generate A␤ 46 and ultimately the secreted A␤ 40/42 . More interestingly, our data demonstrate that ␥-cleavage not only occurs last but also depends on -cleavage occurring prior to it, indicating that -cleavage is crucial for the formation of secreted A␤. Thus, we conclude that the C terminus of secreted A␤ is most likely generated by a series of sequential cleavages, namely first ⑀-cleavage which is then followed by -and ␥-cleavages, and that A␤ 46 produced by -cleavage is the precursor of secreted A␤ 40/42 .The mechanism of the formation of the ␤-amyloid protein (A␤) 2 is the central issue in Alzheimer disease research, not only because A␤ is the major constituent of senile plaques, one of the neuropathological hallmarks of Alzheimer disease, but also because A␤ formation may be a causative event in the disease (1). A␤ is proteolytically derived from a large single transmembrane protein, the ␤-amyloid precursor protein (APP), as a result of sequential cleavages by ␤-and ␥-secretases (1). ␤-Secretase has been identified as a type I membrane aspartyl protease (2, 3). Although the exact nature of ␥-secretase is still a matter of debate, accumulating evidence supports the idea that ␥-secretase is a multiple molecular complex composed of, at least, presenilins, nicastrin, Aph-1, and Pen-2 and that presenilin may function as the catalytic subunit (4).In understanding the mechanism by which the C termini of secreted A␤ are generated during the processing of APP, three major intramembranous cleavages have been established. The first one is the cleavage now specifically referred to as ␥-cleavage (5), which produces the C termini of most of the secreted A␤ species that end at amino acids 40 (A␤40) or 42 (A␤42) of the A␤ sequence. The second one is the ⑀-cleavage occurring between A␤ residues 49 and 50, which produces the N terminus of most of the APP intracellular domain (AICD) (5-8). The identification of this ⑀-cleavage site raises a question as to whether this ⑀-cleavage is obligatory for the generation of the...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

γ-Cleavage Is Dependent on ζ-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain

Zhao

Cui

Mao

et al. 2005

Journal of Biological Chemistry

127

163

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“…In contrast, PS and related proteins have been identified in both metazoans and plants (44)(45)(46)(47)(48). Similar to the genomes of Arabidopsis (Dicot) and Oryza sativa (monocot), whose complete genome sequences are available, an early land plant, the moss Physcomitrella patens, also harbors all four components of ␥-secretase.…”

mentioning

confidence: 99%

Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved

Khandelwal¹,

Chandu²,

Roe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Presenilins (PS) provide the catalytic activity for ␥-secretase, which cleaves physiologically relevant substrates including Notch, ErbB4, and APP. Recent genetic studies indicated that the contribution of PS1 to mouse development includes ␥-secretase-independent functions that cannot be easily explained by any of the demonstrated or hypothesized functions of this protein. To begin a nonbiased analysis of PS1 activity unencumbered by the dominant effect stemming from loss of Notch function, we characterized PS functions in the early land plant Physcomitrella patens, which lacks Notch, ErbB4, and APP. Removal of P. patens PS resulted in phenotypic abnormalities. Further assays performed to delineate the defective pathways in PS-deficient P. patens implicated improper function of the cytoskeletal network. Importantly, this characterization of a nonmetazoan PS uncovered a previously undescribed, evolutionarily conserved function (human PS1 can rescue the growth and light responses) that is ␥-secretase-independent (mutants with substitutions of the catalytic aspartyl residues retain the activity). Introduction of PpPS into PS-deficient mouse embryonic fibroblasts rescues normal growth rates, demonstrating that at least some metazoan functions of PS are evolutionarily conserved.

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“…9 The minimal molecular subunit composition of an enzymatically active g-secretase complex consists of presenilin (either PS-1 or PS-2), nicastrin (Nct), presenilin enhancer 2 (PEN-2) and the anterior pharynx defective 1 protein Aph-1, in mammals Aph-1aS, -1aL or -1b. 10 We further established that the three Aph-1b rat genotypes segregated with a number of behavioral phenotypes. 7 We now generated by crossbreeding, genetic reselection and phenotyping (susceptibility for apomorphine) three lines with one, two or three copies of the Aph-1b gene against an otherwise highly similar general genetic background (I/I, II/II and III/III lines, respectively).…”

Section: Introductionmentioning

confidence: 90%

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

et al. 2006

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Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the c-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about csecretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre-and postnatal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in c-secretase cleavage activity towards one of its best-known substrates, the amyloid-b precursor protein APP. We conclude that the low levels of Aph-1b mRNA and c-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

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Identity and function of γ‐secretase

Cited by 89 publications

References 74 publications

γ-Cleavage Is Dependent on ζ-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain

γ-Cleavage Is Dependent on ζ-Cleavage during the Proteolytic Processing of Amyloid Precursor Protein within Its Transmembrane Domain

Moonlighting activity of presenilin in plants is independent of γ-secretase and evolutionarily conserved

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

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