Unknown

Dataset Information

0

Designed Helical Peptides as Functional Probes for ?-Secretase.


ABSTRACT: ?-Secretase is a membrane-embedded aspartyl protease complex with presenilin as the catalytic component that cleaves within the transmembrane domain (TMD) of >90 known substrates, including the amyloid precursor protein (APP) of Alzheimer's disease. Processing by ?-secretase of the APP TMD produces the amyloid ?-peptide (A?), including the 42-residue variant (A?42) that pathologically deposits in the Alzheimer brain. Complex proteolysis of APP substrate by ?-secretase involves initial endoproteolysis and subsequent carboxypeptidase trimming, resulting in two pathways of A? production: A?49 ? A?46 ? A?43 ? A?40 and A?48 ? A?45 ? A?42 ? A?38. Dominant mutations in APP and presenilin cause early onset familial Alzheimer's disease (FAD). Understanding how ?-secretase processing of APP is altered in FAD is essential for elucidating pathogenic mechanisms in FAD and developing effective therapeutics. To improve our understanding, we designed synthetic APP-based TMD substrates as convenient functional probes for ?-secretase. Installation of the helix-inducing residue ?-aminoisobutyric acid provided full TMD helical substrates while also facilitating their synthesis and increasing the solubility of these highly hydrophobic peptides. Through mass spectrometric analysis of proteolytic products, synthetic substrates were identified that were processed in a manner that reproduced physiological processing of APP substrates. Validation of these substrates was accomplished through mutational variants, including the installation of two natural APP FAD mutations. These FAD mutations also resulted in increased levels of formation of A?-like peptides corresponding to A?45 and longer, raising the question of whether the levels of such long A? peptides are indeed increased and might contribute to FAD pathogenesis.

SUBMITTER: Philip AT 

PROVIDER: S-EPMC7224395 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

Designed Helical Peptides as Functional Probes for γ-Secretase.

Philip Anijamol T AT   Devkota Sujan S   Malvankar Shweta S   Bhattarai Sanjay S   Meneely Kathleen M KM   Williams Todd D TD   Wolfe Michael S MS  

Biochemistry 20191028 44


γ-Secretase is a membrane-embedded aspartyl protease complex with presenilin as the catalytic component that cleaves within the transmembrane domain (TMD) of >90 known substrates, including the amyloid precursor protein (APP) of Alzheimer's disease. Processing by γ-secretase of the APP TMD produces the amyloid β-peptide (Aβ), including the 42-residue variant (Aβ42) that pathologically deposits in the Alzheimer brain. Complex proteolysis of APP substrate by γ-secretase involves initial endoproteo  ...[more]

Similar Datasets

| S-EPMC7359870 | biostudies-literature
| S-EPMC8219260 | biostudies-literature
| S-EPMC3502156 | biostudies-literature
| S-EPMC6110731 | biostudies-literature
| S-EPMC5340309 | biostudies-literature
| S-EPMC3097154 | biostudies-literature
| S-EPMC4115564 | biostudies-literature
| S-EPMC3945338 | biostudies-literature
| S-EPMC7483676 | biostudies-literature
| S-EPMC2678541 | biostudies-literature