What is the role of amyloid precursor protein dimerization?

Khalifa, Naouel Ben; Hees, Joanne Van; Tasiaux, Bernadette; Huysseune, Sandra; Smith, Steven O.; Constantinescu, Stefan N.; Octave, Jean‐Noël; Kienlen‐Campard, Pascal

doi:10.4161/cam.4.2.11476

Cited by 39 publications

(65 citation statements)

References 38 publications

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“…Likewise, APP palmitoylation is initiated in the ER, but pal APP is detected in lipid rafts, which are cholesterol-rich microdomains in Golgi and post-Golgi compartments [4]. APP dimerization is mediated by the extracellular domains E1 or E2, TM domain or by the Aβ containing conserved G 29 XXXG 33 (numbers are based on Aβ numbering) domain ( Reviewed in [21]). APP dimerization via the ectodomain (E1 and E2), in particular, appears to play significant role in APP processing [22].…”

Section: Introductionmentioning

confidence: 99%

Palmitoylated APP Forms Dimers, Cleaved by BACE1

et al. 2016

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A major rate-limiting step for Aβ generation and deposition in Alzheimer’s disease brains is BACE1-mediated cleavage (β-cleavage) of the amyloid precursor protein (APP). We previously reported that APP undergoes palmitoylation at two cysteine residues (Cys186 and Cys187) in the E1-ectodomain. 8–10% of total APP is palmitoylated in vitro and in vivo. Palmitoylated APP (palAPP) shows greater preference for β-cleavage than total APP in detergent resistant lipid rafts. Protein palmitoylation is known to promote protein dimerization. Since dimerization of APP at its E1-ectodomain results in elevated BACE1-mediated cleavage of APP, we have now investigated whether palmitoylation of APP affects its dimerization and whether this leads to elevated β-cleavage of the protein. Here we report that over 90% of palAPP is dimerized while only ~20% of total APP forms dimers. PalAPP-dimers are predominantly cis-oriented while total APP dimerizes in both cis- and trans-orientation. PalAPP forms dimers 4.5-times more efficiently than total APP. Overexpression of the palmitoylating enzymes DHHC7 and DHHC21 that increase palAPP levels and Aβ release, also increased APP dimerization in cells. Conversely, inhibition of APP palmitoylation by pharmacological inhibitors reduced APP-dimerization in coimmunoprecipitation and FLIM/FRET assays. Finally, in vitro BACE1-activity assays demonstrate that palmitoylation-dependent dimerization of APP promotes β-cleavage of APP in lipid-rich detergent resistant cell membranes (DRMs), when compared to total APP. Most importantly, generation of sAPPβ-sAPPβ dimers is dependent on APP-palmitoylation while total sAPPβ generation is not. Since BACE1 shows preference for palAPP dimers over total APP, palAPP dimers may serve as novel targets for effective β-cleavage inhibitors of APP as opposed to BACE1 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Palmitoylated APP Forms Dimers, Cleaved by BACE1

et al. 2016

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“…It has been previously proposed that diminished stability of the Gly-in homodimer inhibits the production of the most toxic Aβ42 isoform (40). We propose that the APP dimer structure diversity could represent an important step in APP processing and play a regulatory role in Aβ isoform distribution (24,41). Independent of the role of homodimers in the cleavage of APP by γ-secretase, our study demonstrates quantitatively that structures of dimers are heterogeneous and that their relative population is modulated by membrane composition as well as sequence.…”

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

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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...

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“…1,14–15 Accordingly, in developing methods for testing for specific heterodimerization of C99 with CD147-CTD we have to consider the possibility that homodimerization of C99 may compete with this process.…”

Section: Introductionmentioning

confidence: 99%

Solution NMR Approaches for Establishing Specificity of Weak Heterodimerization of Membrane Proteins

2011

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Solution NMR provides a powerful approach for detecting complex formation involving weak to moderate intermolecular affinity. However, solution NMR has only rarely been used to detect complex formation between two membrane proteins in model membranes. The impact of specific binding on the NMR spectrum of a membrane protein can be difficult to distinguish from spectral changes that are induced by non-specific binding and/or by changes that arise from forced co-habitation of the two proteins in a single model membrane assembly. This is particularly the case when solubility limits make it impossible to complete a titration to the point of near-saturation of complex formation. In this work experiments are presented that provide the basis for establishing whether specific complex formation occurs between two membrane proteins under conditions where binding is not of high avidity. Application of these methods led to the conclusion that the membrane protein CD147 (also known as EMMPRIN or basigin) forms a specific heterodimeric complex in the membrane with the 99 residue transmembrane C-terminal fragment of the amyloid precursor protein (C99 or APP-βCTF), the latter being the immediate precursor of the amyloid-β polypeptides that are closely linked to the etiology of Alzheimer’s disease.

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What is the role of amyloid precursor protein dimerization?

Cited by 39 publications

References 38 publications

Palmitoylated APP Forms Dimers, Cleaved by BACE1

Palmitoylated APP Forms Dimers, Cleaved by BACE1

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

Solution NMR Approaches for Establishing Specificity of Weak Heterodimerization of Membrane Proteins

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