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. 2023 Oct 3;122(19):3999-4010.
doi: 10.1016/j.bpj.2023.08.025. Epub 2023 Sep 1.

Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition

Conor B Abraham  1 , Lin Xu  1 , George A Pantelopulos  2 , John E Straub  3
Affiliations

Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition

Conor B Abraham et al. Biophys J. .

Abstract

The β-secretase, BACE1, and the α-secretase, ADAM10, are known to competitively cleave amyloid precursor protein (APP) in the amyloid cascades of Alzheimer's disease. Cleavage of APP by BACE1 produces a 99-residue C-terminal peptide (APP-C99) that is subsequently cleaved by γ-secretase to form amyloid-β (Aβ) protein, whereas cleavage of APP by ADAM10 is nonamyloidogenic. It has been speculated that ADAM10/APP and BACE1/APP interactions are regulated by colocalization within and outside of liquid-ordered membrane domains; however, the mechanism of this regulation and the character of the proteins' transmembrane domains are not well understood. In this work, we have developed and characterized minimal congener sequences for the transmembrane domains of ADAM10 and BACE1 using a multiscale modeling approach combining both temperature replica exchange and conventional molecular dynamics simulations based on the coarse-grained Martini2.2 and all-atom CHARMM36 force fields. Our results show that membrane composition impacts the character of the transmembrane domains of BACE1 and ADAM10, adding credence to the speculation that membrane domains are involved in the etiology of Alzheimer's disease.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1
Figure 1
Primary sequences of APP, ADAM10, and BACE1. (A) Cleavage sites on APP by β- (β and β′ sites), α- (α site), and γ-secretase (γ40 and γ42 sites). (B) ADAM10 and (C) BACE1 domains and the TMD congener sequences tested with REMD. The predicted TMDs are highlighted, acidic residues are orange, basic residues are green, polar residues are blue, and nonpolar residues are black. On BACE1, sulfur belt residues are underlined, and S-palmitoylatable residues are marked with circles.
Figure 2
Figure 2
Structural comparison of congener models in implicit membranes. The residue α-helix propensity, pα, and insertion depths, Dins, are presented for (A) ADAM10 and (B) BACE1 TMD and JMD congener models in 30-Å (top), 35-Å (middle), and 40-Å (bottom) GBSW membranes. The insertion depth error bars indicate their standard deviations. The medoid structure of the largest cluster from the agglomerative clustering of each simulation is shown to the right of their Dins and pα results. For both proteins, the residues that induce a hinge/bend in the α-helix are green, and the extracellular JMD is oriented up. For BACE1, S-palmitoylatable residues are blue, and sulfur belt residues are orange.
Figure 3
Figure 3
ADAM10 structure and interactions with membrane. Systems with (A) explicit DIPC membranes or a 35-Å implicit membrane and (B) explicit DPPC membranes or a 40-Å implicit membrane. For each set of membranes, residue insertion depths, Dins, are shown with colored lines (error bars show standard deviations), and gray bars indicate the residues’ α-helix propensities, pα, for the all-atom explicit membrane system (bottom left). Relative lateral atomic densities along the membrane normal, ρ⊥, for lipid phosphate phosphorus atoms and CHOL hydroxyl oxygen atoms (bottom right). Colored bars indicate the average number of hydrogen bonds formed between residues and membrane components (⟨NHB⟩) for the all-atom explicit membrane system (top).
Figure 4
Figure 4
Impact of membrane composition on the orientation of ADAM10. (A) Effect of increase in membrane width on the tilt angle, θ, with confidence ellipses showing the standard deviations. Probability densities of θ and membrane width are shown along their corresponding axes. (B) Tilt angle probability density of all frames from all-atom simulation of ADAM10 in a 7:3 DPPC:CHOL bilayer compared with frames with a hydrogen bond between the sidechain (SC) of H677 and backbone (BB) of W673, and frames with different numbers of hydrogen bonds between the C-terminal JMD and the membrane, NHB(CT-M). (C) Mean orientational angles, ⟨σi⟩, for each residue from all-atom simulations with 9:1 DIPC:CHOL and 7:3 DPPC:CHOL bilayers. (D) Reference graphic depicting θ and σi angles.
Figure 5
Figure 5
ADAM10 principal components and cross correlation matrices. The first (top) and second (bottom) principal components and principal component cross correlation matrices are shown for (A) 9:1 DIPC:CHOL and (B) 7:3 DPPC:CHOL all-atom membranes. The principal components are shown on the structure closest to the mean structure in PC1 and PC2 space. The lengths of the arrows are proportional to the magnitude of the principal components. N-terminus JMD residues are brown, C-terminus JMD residues are gray, W673 and H677 are green, and residue groups 1, 2, and 3 are orange, purple, and cyan, respectively. The cross correlation matrices were constructed using the first 11 principal components for each system to account for over 90% cumulative variance. Gridlines indicate the α-helix and residue groups 1, 2, and 3. Diagonal dashed lines mark the locations of W673 and H677.
Figure 6
Figure 6
BACE1 structure and interactions with membrane. Systems with (A) explicit DIPC membranes or a 35-Å implicit membrane and (B) explicit DPPC membranes or a 40-Å implicit membrane. For each set of membranes, residue insertion depths, Dins, are shown with colored lines (error bars show standard deviations), and gray bars indicate the residues’ α-helix propensities, pα, for the all-atom explicit membrane system (bottom left). Relative lateral atomic densities along the membrane normal, ρ⊥, are shown for lipid phosphate phosphorus atoms and CHOL hydroxyl oxygen atoms (bottom right). Colored bars indicate the average number of hydrogen bonds formed between residues and membrane components (⟨NHB⟩) for the all-atom explicit membrane system (top).
Figure 7
Figure 7
Impact of membrane composition on the orientation of BACE1. (A) Effect of increase in membrane width on the tilt angle, θ, with confidence ellipses showing the standard deviations. Probability densities of θ and membrane width are shown along their corresponding axes. (B) Mean orientational angles, ⟨σi⟩, for each residue from all-atom simulations with 9:1 DIPC:CHOL and 7:3 DPPC:CHOL bilayers.
Figure 8
Figure 8
BACE1 principal components and cross correlation matrices. The first (top) and second (bottom) principal components and principal component cross correlation matrices are shown for (A) 9:1 DIPC:CHOL and (B) 7:3 DPPC:CHOL all-atom membranes. The principal components are shown on the structures closest to the mean structure in PC1 and PC2 space. The lengths of the arrows are proportional to the magnitude of the principal components. C-terminus JMD residues are gray, L468, P472, R481, R484, and R487 are green, and residue groups 1, 2, 3, and 4 are orange, purple, cyan, and pink, respectively. To account for over 90% cumulative variance, the cross correlation matrices for 9:1 DIPC:CHOL and 7:3 DPPC:CHOL were constructed using the first 11 and 10 principal components, respectively. Gridlines indicate the α-helix, and residue groups 1, 2, 3, and 4. Diagonal dashed lines mark the locations of L468, P472, R481, R484, and R487.
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