The dynamics of γ-secretase and its substrates. (September 2020)

• Record Type: Journal Article
• Authors: Hitzenberger, Manuel; Götz, Alexander; Menig, Simon; Brunschweiger, Barbara; Zacharias, Martin; Scharnagl, Christina
• Is Part Of: Seminars in cell & developmental biology. Volume 105(2020)
• Page Start: 86
• Page End: 101
• Publication Date: 2020-09
• Subjects: AA amino acid -- Aβ amyloid-β -- ACE acetyl -- AICD amyloid intracellular domain -- APH1 anterior-pharynx-defective-1 -- APP amyloid-β precursor protein -- CG coarse-grained -- COM center of mass -- cryo-EM cryo-electron microscopy -- DAPT N-[N-(3, 5-Difluorophenacyl)-L-alanyl]-S-phenylglycrine t-Butyl Ester -- DHPC di-hexaonyl phosphatidylcholine -- DMPC di-myristoyl phosphatidylcholine -- DPC dodecyl phosphocholine -- ECD extracellular domain, ectodomain -- E-S complex enzyme-substrate complex -- FAD familial Alzheimer's disease -- GSEC γ-secretase -- H-bonds hydrogen bonds -- ICD intracellular domain -- ITGB1 integrin β1 -- LMPC lyso-myristoyl phosphatidylcholin -- LMPG lyso-myristoyl phosphatidylglycerol -- LRT linear response theory -- MD molecular dynamics -- MMPBSA molecular mechanics Poisson-Boltzmann surface area -- MSF mean square fluctuation -- NCT nicastrin -- NICD NOTCH intracellular domain -- NME N-methyl -- PA phosphatidic acid -- PCA principal component analysis -- PE phosphoethanolamine -- PEN2 presenilin enhancer 2 -- PMF potential of mean force -- POPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine -- PS presenilin -- RMSD root-mean square deviation -- S2P site-2 protease -- SASA solvent accessible surface area -- SPP signal peptide peptidase -- TFE 2.2, 2-trifluoroethanol -- TM transmembrane -- TMD transmembrane domain -- TSA transition-state analogue; Cytology -- Periodicals; Developmental biology -- Periodicals; 571.6
• DOI: 10.1016/j.semcdb.2020.04.008
• Languages: English
• ISSNs: 1084-9521

Abstract

Abstract: γ-Secretase is an intramembrane aspartyl-protease catalyzing the final step in the regulated intramembrane proteolysis of a large number of single-span type-1 transmembrane proteins. The most extensively studied substrates are the amyloid-β precursor protein (APP) and the NOTCH receptors. An important technique for the characterization of interactions and conformational changes enabling γ-secretase to perform hydrolysis within the confines of the membrane are molecular dynamics simulations on different time and length scales. Here, we review structural and dynamical features of γ−secretase and its substrates including flexibility descriptions from simulations and experiments. We address (1) conformational sampling of apo-enzyme and unbound substrates (exemplified for APP, NOTCH1 and the apparent non-substrate integrin β1), (2) substrate recruitment pathways, (3) conformational changes associated with the formation of the recognition complex, (4) cleavage-site unfolding upon interaction with the enzyme's active site, (5) substrate processing after endoproteolysis, and (6) inhibition and modulation of γ-secretase. We conclude with still open questions and suggest further investigations in order to advance our understanding on how γ-secretase selects and processes substrates. This knowledge will improve the ability to better target substrates selectively for therapeutic applications.