Abstract
γ-secretase, an intramembrane-cleaving aspartyl protease is involved in the cleavage of a large number of intramembrane proteins. The most prominent substrate is the amyloid precursor protein, whose proteolytic processing leads to the production of different amyloid Aβ peptides. These peptides are known to form toxic aggregates and may play a key role in Alzheimer's disease (AD). 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. 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. Simulations were performed on the full enzyme complex and on the membrane embedded parts alone. 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. 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. 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. The observed conformational rearrangement allows the interpretation of the effect of several mutations on the activity of γ-secretase. 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.
Highlights
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 γ -Secretase: Atomistic Molecular Dynamics Simulations functional family and due to its proposed role in Alzheimer’s disease (AD) the most studied one (De Strooper et al, 2012; Fukumori and Steiner, 2016)
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) indicating that one role of this protein complex is the removal of partially degraded proteins from the membrane, thereby preventing their accumulation
Since the NIC ECD consists of many mobile loop regions, it naturally exhibits larger deviations than the transmembrane domain (TMD) situated in the lipid bilayer
Summary
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 γ -Secretase: Atomistic Molecular Dynamics Simulations functional family and due to its proposed role in Alzheimer’s disease (AD) the most studied one (De Strooper et al, 2012; Fukumori and Steiner, 2016). C99 is the C-terminal fragment of the amyloid precursor protein (APP) and results from the removal of large parts of the APP ectodomain (Zhang et al, 2011). This preprocessing step, in the case of APP mediated by β-secretase (Vassar et al, 1999), is necessary for sterical reasons: Proteins possessing large soluble extracellular domains are unable to get into close contact with the active site of g-sec (Bai et al, 2015b; Langosch et al, 2015; Langosch and Steiner, 2017). The biological role of APP is mostly in the dark (Deyts et al, 2016) but it is well established that sequential C99 processing results in an intracellular peptide (AICD), several short (mostly three amino acid long) peptides and the Aβ40/42/43/46 fragments (Bolduc et al, 2016)
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