Research ArticleBIOCHEMISTRY

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

+ See all authors and affiliations

Science Advances  12 Apr 2017:
Vol. 3, no. 4, e1602794
DOI: 10.1126/sciadv.1602794

You are currently viewing the abstract.

View Full Text

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.

Keywords
  • Notch
  • receptor
  • transmembrane domain
  • C99
  • amyloid precursor protein
  • NMR
  • structure
  • bicelles
  • cholesterol
  • Membrane

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

View Full Text