Structural and Biochemical Differences Between the Notch and the Amyloid Precursor Protein Transmembrane Domains

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2017 Apr 26

PMID 28439555

Citations 20

Authors

Catherine L Deatherage

Zhenwei Lu

Brett M Kroncke

Sirui Ma

Jarrod A Smith

Markus W Voehler

Robert L McFeeters

Charles R Sanders

Affiliations

Soon will be listed here.

Abstract

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 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.

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