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. 2018 Nov 7;20(43):27294-27304.
doi: 10.1039/c8cp04138e.

Influence of membrane lipid composition on the structure and activity of γ-secretase

Rodrigo Aguayo-Ortiz  1 , John E Straub, Laura Dominguez
Affiliations

Influence of membrane lipid composition on the structure and activity of γ-secretase

Rodrigo Aguayo-Ortiz et al. Phys Chem Chem Phys. .

Abstract

γ-Secretase (GS) is a multi-subunit membrane-embedded aspartyl protease that cleaves more than 80 integral membrane proteins, including the amyloid precursor protein (APP) to produce the amyloid-β (Aβ) peptide. Oligomerization and aggregation of the 42-amino acid length Aβ isoform in the brain has been associated with the development and progression of Alzheimer's disease (AD). Based on recent experimental structural studies and using multiscale computational modeling approaches, the conformational states and protein-membrane interactions of the GS complex embedded in six homogeneous and six heterogeneous lipid bilayers were characterized. In order to identify potential lipid and cholesterol binding sites, GS regions with high lipid/cholesterol occupancy values were analyzed using atomistic and coarse-grained simulations. Long lipid residence times were observed to be correlated with a large number of hydrogen bonds between the charged headgroups and key GS amino acids. This observation provides a plausible explanation for the inhibition of GS by charged lipids observed in previous experimental studies. Computed lateral pressure profiles suggest that higher transmembrane pressures favor active state conformations of the catalytic subunit. A probable mechanism for the regulation of the local stress response in cholesterol-rich multicomponent lipid bilayers is identified. Finally, it is demonstrated that interactions between the nicastrin extracellular domain and lipid headgroups leads to a compact structural conformation of the GS complex. Overall, this study provides valuable insight into the effect of bilayer lipid composition on the GS structural ensemble and its function.

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Conflict of interest statement

Conflicts of interest

There are no conflicts to declare.

Figures

Figure 1.
Figure 1.
Overview of the GS structure. (A) Depiction of γ-secretase structure derived from 5FN2 PDB structure colored by its four components: NCT (violet), PS1 (green), APH-1A (orange) and PEN-2 (yellow), highlighting the catalytic aspartic residues (red). (B) Hydrophobic (yellow) and hydrophilic (teal) residue distribution in the GS surface. (C) Depiction of the hydropathy index distribution ranging from the most (blue) to the least hydrophilic (red) regions. (D) Distribution of the negatively (red) and positively (blue) charged amino acids in the GS.
Figure 2.
Figure 2.
Effect of the headgroup charge (POPC, POPE, and POPA) and membrane thickness (DLPC, DPPC, and DGPC) in the structural ensemble of 5FN2 derived CG models. (A) System density and lateral pressure (LP) profiles as a function of lipid composition. The dashed black line shows the POPC lateral pressure profile and the gray background depicts the headgroups (dark gray) and tails (light gray) of the lipids in the bilayer. (B) Distribution of our 20 replicas CG simulations projected onto the distances between the catalytic residues (D257 and D385) and the calculated TM6 tilt angles in the unprotonated and protonated states of Asp385. The colored scale on the right defines the relative populations. The black circles mark the locations of the experimental GS structures at CG resolution after backbone-restrained minimization (PDB IDs: 5A63, 4UIS, 5FN2, 5FN3, 5FN4 and 5FN5).– (C) Representation of lipid displacement in the upper (UL) and lower (LL) leaflets of the lipid bilayer relative to GS (purple). The intensity of the color in both leaflets indicates the smaller (white) and greater (colored) displacement of the lipids in the three simulated membranes. The figure on the left depicts the perspective of the GS complex used for the graphs of lipid displacement and membrane thickness (C and D). Also shown are the proposed initial substrate-binding sites (SBS1 and SBS2). (D) Local membrane thickness analysis of DLPC, DPPC and DGPC lipid bilayers.
Figure 3.
Figure 3.
Atomistic simulations of GS embedded in charged lipid bilayers. (A) Occupancy plots of POPC, POPE and POPA lipids located in the upper and lower leaflets in contact with GS for more than 70% of the time during the last 100 ns of the all atom simulations. The colored scale on the right defines occupancy values of lipids with higher residence times during the last 100ns of simulation. (B) Three-dimensional density distribution of selected POPC lipids with high residence times around GS shown from forward (left) and rear (right) views. The substrate (SBS) and lipid binding sites (LBS) are highlighted in red and blue, respectively. (C) Time evolution of POPC, POPE and POPA membrane thickness (Top) and the minimum distance between the catalytic aspartates and the lipid headgroup (Bottom) through the last 100 ns of our all-atom MD simulations. (D) Depiction of POPE (purple) lipid interactions with PS1 (green) at LBS1 and LBS2. The dotted lines represent proper hydrogen bond distances.
Figure 4.
Figure 4.
Changes in GS dynamics in POPC bilayers containing 20%, 40%, and 60% of cholesterol (CHOL). (A) Lateral pressure profiles as a function of cholesterol concentration. The dashed black line shows the POPC lateral pressure profile without CHOL and the gray background marks the location of the headgroups (dark gray) and tails (light gray) of the membrane. (B) Distribution of the 20 replicas CG simulations projected onto the distances between catalytic residues (Asp257 and Asp385) and the calculated TM6 tilt angles in the protonated state of Asp385. The colored scale defines the relative populations. The black circles depict the values obtained from experimental structures of GS at CG resolution after backbone-restrained minimization (PDB IDs: 5A63, 4UIS, 5FN2, 5FN3, 5FN4 and 5FN5). (C) Local membrane thickness analysis of the CG membranes with different POPC:CHOL mixtures. (D) Lipid occupancy plots for CHOL in the AA MD simulation located in the upper and lower leaflets of our POPC lipid bilayer systems. The colored scale defines the occupancy of the CHOL molecules with higher residence times. (Right) Structure of CHOL molecule interacting with NCT and APH-1A components. (E) Per amino acid occupancy contacts of CHOL with each GS subunit in our AA simulated systems. (F) Depiction of amino acids that achieved the greatest number of contacts with CHOL molecules, constituting the CHOL binding sites (CBS).
Figure 5.
Figure 5.
(A) Lateral pressure profiles of three different lipid raft systems. The dashed black line shows the POPC lateral pressure profile without CHOL and the gray background depicts the headgroups (dark gray) and tails (light gray) of the membrane. (B) Distribution of the 20 replicas CG simulations of Raft 1 projected onto the distances between the catalytic residues (Asp257 and Asp385) and the calculated TM6 tilt angles in the protonated state of Asp385. The colored scale defines the relative populations. The black circles depict the values obtained from experimental structures of GS at CG resolution after backbone-restrained minimization (PDB IDs: 5A63, 4UIS, 5FN2, 5FN3, 5FN4 and 5FN5). (C) Local membrane thickness analysis of Raft 1. (D) Distribution of major axis length of the GS complex embedded in the twelve different membrane systems from the CG replica simulations (see Table 1). The gray line indicates the GS major axis lengths employed to classify our GS structures in an intermediate (In) conformation, while the upper and lower white zones display GS lengths in extended (Ex) and compact (Co) forms, respectively.
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