Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site

Chen, Wen; Gamache, Eric R.; Rosenman, David J.; Xie, Jierui; López, Marı́a M.; Li, Yueming; Wang, Chunyu

doi:10.1038/ncomms4037

Cited by 77 publications

(151 citation statements)

References 44 publications

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…The trends observed in the structural ensemble of the C99 23−55 homodimer as a function of lipid membrane composition also provide a partial explanation for the recently observed NMR structure of the C99 23−55 homodimer in DPC micelle (23,42). The structure of C99 15−55 was observed to have a Gly-out topology that differed from the previously proposed Gly-in structures that were based on simulation and solid-state NMR data (7,8,(43)(44)(45).…”

Section: Discussionmentioning

confidence: 58%

“…Membrane thickness impacts the processing of APP by γ-secretase and affects the overall production of Aβ peptide and the ratio of Aβ 40 :Aβ 42 . Our results demonstrate that membrane composition does influence membrane thickness, which can alter both the depth of insertion of the peptide into the membrane, and impact the termination of processive cleavage of the TM helix by γ-secretase.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein

Domı́nguez

Foster

Straub

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

View full text Add to dashboard Cite

Cleavage of the amyloid precursor protein (APP) by γ-secretase is a crucial first step in the evolution of Alzheimer's disease. To discover the cleavage mechanism, it is urgent to predict the structures of APP monomers and dimers in varying membrane environments. We determined the structures of the C99 23−55 monomer and homodimer as a function of membrane lipid composition using a multiscale simulation approach that blends atomistic and coarsegrained models. We demonstrate that the C99 23−55 homodimer structures form a heterogeneous ensemble with multiple conformational states, each stabilized by characteristic interpeptide interactions. The relative probabilities of each conformational state are sensitive to the membrane environment, leading to substantial variation in homodimer peptide structure as a function of membrane lipid composition or the presence of an anionic lipid environment. In contrast, the helicity of the transmembrane domain of monomeric C99 1−55 is relatively insensitive to the membrane lipid composition, in agreement with experimental observations. The dimer structures of human EphA2 receptor depend on the lipid environment, which we show is linked to the location of the structural motifs in the dimer interface, thereby establishing that both sequence and membrane composition modulate the complete energy landscape of membrane-bound proteins. As a by-product of our work, we explain the discrepancy in structures predicted for C99 congener homodimers in membrane and micelle environments. Our study provides insight into the observed dependence of C99 protein cleavage by γ-secretase, critical to the formation of amyloid-β protein, on membrane thickness and lipid composition.nderstanding the structural and thermodynamic properties of transmembrane (TM) helical dimers is of fundamental importance to molecular biology. It is known that the association of "bitopic" proteins, having single pass TM helical domains, is essential to immunoreceptors and protein kinases that play critical roles in cellular function. Computational and experimental studies have provided insight into the role of sequence-specific interactions stabilizing helix dimerization (1, 2). Examples include the heptad repeat motif responsible for the stability of coiled-coils in GCN4 phospholamban (3) and the M2 proton channel (4), the role of the GxxxG motif in stabilizing TM helix-helix association in systems including the glycophorin A (GpA) homodimer (5, 6), found in the human erythrocyte membrane, and GxxxG and heptad repeat motifs, which play a role in stabilizing homodimers of APP-C99 (C99), the 99-aa C-terminal fragment of the amyloid precursor protein (APP) (7,8).The amyloid β (Aβ) peptide aggregation pathway, known to be crucial to the evolution of Alzheimer's disease (AD), begins with the cleavage of C99 by γ-secretase leading to the formation of a number of isoforms of Aβ. The formation of homodimers of C99 has been proposed to be critical to the mechanism by which C99 is cleaved by γ-secretase, a process that is known to dep...

show abstract

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein

Domı́nguez

Foster

Straub

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

View full text Add to dashboard Cite

show abstract

“…CSPs for Lys 16 may be explained by a recent docking study involving sulindac sulfide and A␤ fibrils that suggested that sulindac sulfide may bind weakly to a shallow, solvent-exposed pocket in the vicinity of Lys 16 and Val 18 and does not interfere with fibrillation (30). This binding mode may, in addition, account for the large REDOR signal detected for the overlapping resonances Val 18 /Val 39 C␥ (Fig.…”

Section: Discussionmentioning

confidence: 95%

“…Solution-state NMR structures of the APP-TM (transmembrane) dimer have been solved for the wild-type (17) and a familial mutant (18). NMR and EPR experiments have revealed a potential cholesterol-binding site within the C-terminal Cys 99 sequence and highlight the significance of the GXXXG segments for binding (19).…”

mentioning

confidence: 99%

Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide

Prade

Bittner

Sarkar

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The mechanism of interaction between small molecules and amyloid-␤ fibrils is unknown. Results: Molecular modeling on the basis of solid-state NMR reveals that sulindac sulfide intercalates between ␤-strands of amyloid-␤ fibrils. Conclusion: Sulindac sulfide interacts with amyloid-␤ fibrils in a specific manner and binds to hydrophobic cavities in the core of the fibrils. Significance: Unraveling how small molecules interfere with amyloidogenic deposits will assist structure-based drug design for neurodegenerative disorders.

show abstract

“…As an initial structure of APP, we used the NMR structure registered in Protein Data Bank (PDB) (PDB ID: 2LZ3 [33]). This structure is a partial structure of APP770 and composed of the 28 amino acids from the Lys699 to Lys726 residues of APP770.…”

Section: Construction Of Stable Structures For App + Curcumin Complexesmentioning

confidence: 99%

Specific interactions between amyloid-β peptide and curcumin derivatives: Ab initio molecular simulations

Ishimura

Kadoya

Suzuki

et al. 2015

Chemical Physics Letters

View full text Add to dashboard Cite

Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site

Cited by 77 publications

References 44 publications

Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein

Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein

Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide

Specific interactions between amyloid-β peptide and curcumin derivatives: Ab initio molecular simulations

Contact Info

Product

Resources

About