Unknown

Dataset Information

0

Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains.

ABSTRACT: ?-Secretase cleavage of the Notch receptor transmembrane domain is a critical signaling event for various cellular processes. Efforts to develop inhibitors of ?-secretase cleavage of the amyloid-? precursor C99 protein as potential Alzheimer's disease therapeutics have been confounded by toxicity resulting from the inhibition of normal cleavage of Notch. We present biochemical and structural data for the combined transmembrane and juxtamembrane Notch domains (Notch-TMD) that illuminate Notch signaling and that can be compared and contrasted with the corresponding traits of C99. The Notch-TMD and C99 have very different conformations, adapt differently to changes in model membrane hydrophobic span, and exhibit different cholesterol-binding properties. These differences may be exploited in the design of agents that inhibit cleavage of C99 while allowing Notch cleavage.

SUBMITTER: Deatherage CL 

PROVIDER: S-EPMC5389784 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains.

Deatherage Catherine L CL   Lu Zhenwei Z   Kroncke Brett M BM   Ma Sirui S   Smith Jarrod A JA   Voehler Markus W MW   McFeeters Robert L RL   Sanders Charles R CR  

Science advances 20170412 4

γ-Secretase cleavage of the Notch receptor transmembrane domain is a critical signaling event for various cellular processes. Efforts to develop inhibitors of γ-secretase cleavage of the amyloid-β precursor C99 protein as potential Alzheimer's disease therapeutics have been confounded by toxicity resulting from the inhibition of normal cleavage of Notch. We present biochemical and structural data for the combined transmembrane and juxtamembrane Notch domains (Notch-TMD) that illuminate Notch sig  ...[more]

Similar Datasets

Unknown Co-localization of the amyloid precursor protein and Notch intracellular domains in nuclear transcription factories.
| S-EPMC2868363 | biostudies-literature
Unknown Structural heterogeneity in transmembrane amyloid precursor protein homodimer is a consequence of environmental selection.
| S-EPMC4105063 | biostudies-literature
Unknown Structural Characterization of the Amyloid Precursor Protein Transmembrane Domain and Its γ-Cleavage Site.
| S-EPMC6645296 | biostudies-literature
Unknown Transmembrane fragment structures of amyloid precursor protein depend on membrane surface curvature.
| S-EPMC3928069 | biostudies-literature
Unknown The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.
| S-EPMC3528355 | biostudies-literature
Unknown Structural and functional alterations in amyloid-? precursor protein induced by amyloid-? peptides.
| S-EPMC4001850 | biostudies-literature
Unknown SorLA complement-type repeat domains protect the amyloid precursor protein against processing.
| S-EPMC4319007 | biostudies-literature
Unknown Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor?
| S-EPMC2572687 | biostudies-literature
Unknown Amyloid precursor protein and amyloid precursor-like protein 2 in cancer.
| S-EPMC4991393 | biostudies-literature
Unknown Transmembrane structures of amyloid precursor protein dimer predicted by replica-exchange molecular dynamics simulations.
| S-EPMC2727648 | biostudies-literature