Conformationally Flexible Sites within the Transmembrane Helices of Amyloid Precursor Protein and Notch1 Receptor

Biochemistry. 2019 Jul 16;58(28):3065-3068. doi: 10.1021/acs.biochem.9b00505. Epub 2019 Jul 8.

Abstract

Intramembrane proteases typically cleave multiple substrates within their transmembrane domains (TMDs). Because substrate TMDs lack a consensus sequence around their scissile sites, it remains unclear how the enzyme discriminates substrates from nonsubstrates at the level of their TMDs. Here, we compare the previously well investigated TMDs of γ-secretase substrates C99 and Notch1 in terms of helix flexibility. Our results reveal that the low-stability site neigboring a functionally relevant diglycine hinge of C99 has an equivalent in the Notch1 TMD. This suggests that the tetra-alanine motif of Notch1 also functions as a hinge which may facilitate its cleavage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / genetics
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Protein Conformation
  • Protein Domains / genetics
  • Protein Structure, Secondary
  • Receptor, Notch1 / chemistry*
  • Receptor, Notch1 / genetics

Substances

  • Amyloid beta-Protein Precursor
  • NOTCH1 protein, human
  • Peptide Fragments
  • Receptor, Notch1
  • amyloid beta-protein precursor C-terminal fragment beta, human