The most thoroughly investigated ( Langosch et al., 2015 Langosch and Steiner, 2017) target of g-sec mediated cleavage is C99, containing a single-span transmembrane alpha-helix. It has been established that g-sec is able to process a large number of substrates ( Beel and Sanders, 2008 Haapasalo and Kovacs, 2011 Langosch et al., 2015) (as of today more than 90 potential substrate molecules are known Langosch et al., 2015) indicating that one role of this protein complex is the removal of partially degraded proteins from the membrane, thereby preventing their accumulation. The protein complex γ-secretase (g-sec) is the only known intramembrane protease requiring an elaborate interplay between four different proteins: nicastrin (NIC), presenilin (PS), anterior pharynx-defective-1 (APH-1) and presenilin enhancer-2 (PEN-2) ( Bai et al., 2015a, b Langosch et al., 2015 Langosch and Steiner, 2017), rendering it the structurally most complex member of this functional family and due to its proposed role in Alzheimer's disease (AD) also the most studied one ( De Strooper et al., 2012 Fukumori and Steiner, 2016).
A number of long-lived lipid binding sites could be identified on the membrane spanning surface of γ-secretase which may coincide with association regions of hydrophobic membrane helices to form putative substrate binding exosites. The observed conformational rearrangement allows the interpretation of the effect of several mutations on the activity of γ-secretase. This conformational change is associated with a distinct rearrangement of transmembrane helices, a global compaction of the catalytically active presenilin subunit a change in the water structure near the active site and a rigidification of the protein fold. During the simulation on the membrane spanning part a transition between an inactive conformation (with catalytic residues far apart) toward a putatively active form (with catalytic residues in close proximity) has been observed. The simulations revealed global motions compatible with the experimental enzyme structures and indicated little dependence of the dynamics of the transmembrane domains on the soluble extracellular subunits.
#Alone in the dark ps1 water full#
Simulations were performed on the full enzyme complex and on the membrane embedded parts alone. We have used molecular dynamics (MD) simulations to study the global dynamics and conformational transitions of γ-secretase, as well as the water and lipid distributions in and around the transmembrane domains in atomic detail. Recently, the three-dimensional structure of γ-secretase has been determined via Cryo-EM, elucidating the spatial geometry of this enzyme complex in different functional states. These peptides are known to form toxic aggregates and may play a key role in Alzheimer's disease (AD). The most prominent substrate is the amyloid precursor protein, whose proteolytic processing leads to the production of different amyloid Aβ peptides. Γ-secretase, an intramembrane-cleaving aspartyl protease is involved in the cleavage of a large number of intramembrane proteins.
Physics Department T38, Technical University of Munich, Garching, Germany.Manuel Hitzenberger * and Martin Zacharias
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