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Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and ?-secretase processing of the C99 peptide.

ABSTRACT: Extracellular deposition of ?-amyloid (A?) peptides in the brain is a hallmark of Alzheimer's disease (AD). Upon ?-secretase-mediated cleavage of the ? C-terminal fragment (?-CTF) from the A? precursor protein, the ?-secretase complex produces the A? peptides associated with AD. The familial T43I mutation within the transmembrane domain of the ?-CTF (also referred to as C99) increases the ratio between the A?42 and A?40 peptides largely due to a decrease in A?40 formation. A?42 is the principal component of amyloid deposits within the brain parenchyma, and an increase in the A?42/A?40 ratio is correlated with early-onset AD. Using NMR and FTIR spectroscopy, here we addressed how the T43I substitution influences the structure of C55, the minimal sequence containing the entire extracellular and transmembrane (TM) domains of C99 needed for ?-secretase processing. ¹³C NMR chemical shifts indicated that the T43I substitution increases helical structure within the TM domain of C55. These structural changes were associated with a shift of the C55 dimer to the monomer and an increase in the tilt of the TM helix relative to the membrane normal in the T43I mutant compared with that of WT C55. The A21G (Flemish) mutation was previously found to increase secreted A?40 levels; here, we combined this mutation in the extracellular domain of C99 with T43I and observed that the T43I/A21G double mutant decreases A?40 formation. We discuss how the observed structural changes in the T43I mutant may decrease A?40 formation and increase the A?42/A?40 ratio.

SUBMITTER: Tang TC

PROVIDER: S-EPMC6463720 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide.

Tang Tzu-Chun TC Kienlen-Campard Pascal P Hu Yi Y Perrin Florian F Opsomer Rémi R Octave Jean-Noël JN Constantinescu Stefan N SN Smith Steven O SO

The Journal of biological chemistry 20190212 15

Extracellular deposition of β-amyloid (Aβ) peptides in the brain is a hallmark of Alzheimer's disease (AD). Upon β-secretase-mediated cleavage of the β C-terminal fragment (β-CTF) from the Aβ precursor protein, the γ-secretase complex produces the Aβ peptides associated with AD. The familial T43I mutation within the transmembrane domain of the β-CTF (also referred to as C99) increases the ratio between the Aβ42 and Aβ40 peptides largely due to a decrease in Aβ40 formation. Aβ42 is the principal ...[more]

PMID: 30755484

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Project description:The amyloid ?-peptide (A?) of Alzheimer's disease (AD) is generated by proteolysis within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid ? protein-precursor (APP CTF?) by the ?-secretase complex. This processing produces A? ranging from 38 to 49 residues in length. Evidence suggests that this spectrum of A? peptides is the result of successive ?-secretase cleavages, with endoproteolysis first occurring at the ? sites to generate A?48 or A?49, followed by C-terminal trimming mostly every three residues along two product lines to generate shorter, secreted forms of A?: the primary A?49-46-43-40 line and a minor A?48-45-42-38 line. The major secreted A? species are A?40 and A?42, and an increased proportion of the longer, aggregation-prone A?42 compared to A?40 is widely thought to be important in AD pathogenesis. We examined TMD substrate determinants of the specificity and efficiency of ? site endoproteolysis and carboxypeptidase trimming of CTF? by ?-secretase. We determined that the C-terminal negative charge of the intermediate A?49 does not play a role in its trimming by ?-secretase. Peptidomimetic probes suggest that ?-secretase has S1', S2', and S3' pockets, through which trimming by tripeptides may be determined. However, deletion of residues around the ? sites demonstrates that a depth of three residues within the TMD is not a determinant of the location of endoproteolytic ? cleavage of CTF?. We also show that instability of the CTF? TMD helix near the ? site significantly increases endoproteolysis, and that helical instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by ?-secretase. In addition, we found that CTF? dimers are not endoproteolyzed by ?-secretase. These results support a model in which initial interaction of the array of residues along the undimerized single helical TMD of substrates dictates the site of initial ? cleavage and that helix unwinding is essential for both endoproteolysis and carboxypeptidase trimming.

Project description:The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by ?-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor ?-secretase reaction product (A?42) to that of the major reaction product (A?40). Although no PS1 mutations are present, altered A?42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of A?42 as amyloid.Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP ?-secretases and ?-secretases, yielding a fragment that we have named p3-Alc(?) because of the parallel genesis of p3-Alc(?) peptides and the p3 fragment of APP. As with A?, both major and minor p3-Alc(?) s are generated. We studied the alternative processing of p3-Alc(?) in various clinical populations.We previously reported that changes in the A?42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(?) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(?) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(?) variant, p3-Alc(?) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts.These results suggest that some SAD may involve alternative processing of multiple ?-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve ?-secretase dysfunction.

Dataset Information

Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and ?-secretase processing of the C99 peptide.

Publications

Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide.

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