Alzheimer Presenilin-1 Mutations Dramatically Reduce Trimming of Long Amyloid β-Peptides (Aβ) by γ-Secretase to Increase 42-to-40-Residue Aβ

Fernandez, Marty A.; Klutkowski, Julia A.; Freret, Thomas; Wolfe, Michael S.

doi:10.1074/jbc.m114.581165

Cited by 136 publications

(125 citation statements)

References 36 publications

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“…Indeed, K m values of ≤1 μM have been reported for APP-, APLP-, ErbB4-, and N-cadheren-based substrates as well as notch (44,56,57). This apparently strong interaction between substrate TMD and γ-secretase is in stark contrast to the binding between rhomboid and its substrate, where no physiologically relevant binding affinity between the two is observed.…”

Section: Discussionmentioning

confidence: 56%

Nicastrin functions to sterically hinder γ-secretase–substrate interactions driven by substrate transmembrane domain

Bolduc

Montagna

et al. 2015

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

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129

152

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γ-Secretase is an intramembrane-cleaving protease that processes many type-I integral membrane proteins within the lipid bilayer, an event preceded by shedding of most of the substrate's ectodomain by α-or β-secretases. The mechanism by which γ-secretase selectively recognizes and recruits ectodomain-shed substrates for catalysis remains unclear. In contrast to previous reports that substrate is actively recruited for catalysis when its remaining short ectodomain interacts with the nicastrin component of γ-secretase, we find that substrate ectodomain is entirely dispensable for cleavage. Instead, γ-secretase-substrate binding is driven by an apparent tight-binding interaction derived from substrate transmembrane domain, a mechanism in stark contrast to rhomboid-another family of intramembrane-cleaving proteases. Disruption of the nicastrin fold allows for more efficient cleavage of substrates retaining longer ectodomains, indicating that nicastrin actively excludes larger substrates through steric hindrance, thus serving as a molecular gatekeeper for substrate binding and catalysis.

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Section: Discussionmentioning

confidence: 56%

Nicastrin functions to sterically hinder γ-secretase–substrate interactions driven by substrate transmembrane domain

Bolduc

Montagna

et al. 2015

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

Self Cite

129

152

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“…For example, Aβ43 was reported to exhibit more potent amyloidogenicity and pathogenicity (34). Existing data suggest that absolute levels of Aβ42 are not as important as the altered ratios of the Aβ peptides, most notably the ratio of Aβ42/Aβ40 (22,33,35). These considerations have significant ramifications on the discovery of novel drugs that may target mutant γ-secretases.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, in all cases, the cleavage reactions were carried out in detergent micelles, as opposed to lipid bilayers or liposomes. Published results show little difference for reactions performed in detergent micelles versus lipid bilayers (33).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH

Dang

Wang

et al. 2015

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

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Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of γ-secretase), making modulation of γ-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact γ-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to γ-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Aβ42, Aβ40, and Aβ38. The molar ratio of the cleavage products Aβ42 over Aβ40 by PSH is nearly identical to that by γ-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of γ-secretase also modulate PSH similarly in terms of the Aβ42/Aβ40 ratio. Structural analysis reveals association of a known γ-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of γ-secretase.A myloid precursor protein (APP) is initially cleaved by β-secretase in the extracellular space, producing a membrane-tethered, 99-residue carboxyl-terminal fragment known as APP C99 (1). APP C99 then undergoes sequential cleavages by γ-secretase, first at the e sites, yielding Aβ49/Aβ48, and eventually at the γ-sites, generating Aβ42/Aβ40/Aβ38 (2-4) (Fig. 1A). The 230-kDa γ-secretase contains four components: presenilin (PS), Pen-2, Aph-1, and nicastrin (NCT), of which PS1 is the target of most mutations derived from early-onset familial Alzheimer's disease (FAD) patients. Rather than abolishing the protease activity of γ-secretase, these mutations are thought to increase the molar ratio of Aβ42 over Aβ40 (2).Among the cleavage products of γ-secretase, Aβ42 is particularly prone to aggregation, leading to formation of β-amyloid plaque in the brain and presumably causing Alzheimer's disease (3). Other FAD-derived mutations map to APP and PS2, lending support to the causal relationship between formation of β-amyloid plaque and Alzheimer's disease (5). Therapeutic intervention of Alzheimer's disease may directly benefit from in vitro investigation of γ-secretase and discovery of its potential modulators (6). Unfortunately, such effort has been hampered by the difficulty in expression, purification, and manipulation of the complex protease. This problem persists despite recent breakthroughs in structural elucidation of γ-secretase and nicastrin (7,8).The intramembrane aspartate protease PSH from the archaeon Methanoculleus marisnigri JR1 shares 19% sequence identity and 53% sequence similarity with human PS1 (hPS1). The signature motifs for catalysis, ΦYDΦΦ (Φ for a hydrophobic residue) on transmembrane segment 6 (TM6) and ΦGΦGD on TM7, are identical between PSH and hPS1. PSH can be readily overexpressed in Escheri...

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“…Moreover, in vitro and cell internal PSEN / γ-secretase offer additional degradation pathway: Aβ 43 → Aβ 38 .In contrast, the PSEN mutant acts on γ-secretase by inhibiting the degradation of longer Aβ. PSEN / γ-secretase can minimize the functional loss of Aβ42 and Aβ43, which could in turn help to prevent AD [76].…”

Section: Mutations In Psen Psen-1 and Psen-2mentioning

confidence: 99%