Impact of Bilayer Lipid Composition on the Structure and Topology of the Transmembrane Amyloid Precursor C99 Protein

Song, Yuanli; Mittendorf, Kathleen F.; Lu, Zhenwei; Sanders, Charles R.

doi:10.1021/ja4114374

Cited by 53 publications

(84 citation statements)

References 32 publications

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“…Bicelles have been employed to study a variety of membrane-associated proteins in their active forms [69–72]. Vlach and Saad showed that titration of HIV-1 MA with 1,2-dihexanoyl- sn -glycero-3-phosphocholine (DHPC) micelles and DMPC/DHPC bicelles caused NMR chemical shift perturbations consistent with membrane-promoted exposure of the myristoyl group [61].…”

Section: Resultsmentioning

confidence: 99%

Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein

Mercredi

Bucca

Loeliger

et al. 2016

Journal of Molecular Biology

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118

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Assembly of HIV-1 particles is initiated by the trafficking of viral Gag polyproteins from the cytoplasm to the plasma membrane (PM), where they co-localize and bud to form immature particles. Membrane targeting is mediated by the N-terminally myristoylated matrix (MA) domain of Gag and is dependent on the PM marker phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Recent studies revealed that PI(4,5)P2 molecules containing truncated acyl chains [tr-PI(4,5)P2] are capable of binding MA in an “extended lipid” conformation and promoting myristoyl exposure. Here we report that tr-PI(4,5)P2 molecules also readily bind to non-membrane proteins, including HIV-1 capsid (CA), which prompted us to re-examine MA-PI(4,5)P2 interactions using native lipids and membrane mimetic liposomes and bicelles. Liposome binding trends observed using a recently developed NMR approach paralleled results of flotation assays, although the affinities measured under the equilibrium conditions of NMR experiments were significantly higher. Native PI(4,5)P2 enhanced MA binding to liposomes designed to mimic non-raft-like regions of the membrane, supporting proposals that Gag binding may nucleate raft formation. Studies with bicelles revealed a subset of surface and myr-associated MA residues that are sensitive to native PI(4,5)P2, but cleft residues that interact with the 2′-acyl chains of tr-PI(4,5)P2 molecules in aqueous solution were insensitive to native PI(4,5)P2 in bicelles. Our findings call to question extended-lipid MA:membrane binding models, and instead support a model put forward from coarse-grained simulations indicating that binding is mediated predominantly by dynamic, electrostatic interactions between conserved basic residues of MA and multiple PI(4,5)P2 and phosphatidylserine molecules.

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Section: Resultsmentioning

confidence: 99%

Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein

Mercredi

Bucca

Loeliger

et al. 2016

Journal of Molecular Biology

Self Cite

118

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“…On the other hand, structures of C99 1−99 monomer peptide in LMPG micelles and in a series of five zwitterionic bicelle compositions (phosphatidylcholine and sphingomyelin where the acyl chain lengths varied from 14 to 24 carbons) suggest that the helicity of the TM domain of C99 is relatively insensitive to membrane lipid composition (22,28). These contrasting conclusions for the structures of both the monomers and dimers raise important questions related to the role of environment in modulating C99 monomer structure and C99 homodimer structure and stability.…”

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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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“…This 418 might be related to the processive cleavage by the γ-secretase, as flexi-419 bility allows the helix to adopt to the sluice-like active site of the prote-420 ase[146][147][148][149]. Importantly, the proteolytic efficiency is enhanced 2-4 421 fold in the presence of cholesterol[150].422In recent studies a cholesterol-binding site and a homodimerization 423 interface at C99 were defined[146,[151][152][153]. Homodimerization and 424 cholesterol binding were found to compete, as both involve the glycine 425 zipper motif G 700 xxxG 704 xxxG 708 G 709[151] (Fig.…”

mentioning

confidence: 99%

Functional competition within a membrane: Lipid recognition vs. transmembrane helix oligomerization

Stangl

Schneider

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Binding of specific lipids to large, polytopic membrane proteins is well described, and it is clear that such lipids are crucial for protein stability and activity. In contrast, binding of defined lipid species to individual transmembrane helices and regulation of transmembrane helix monomer-oligomer equilibria by binding of distinct lipids is a concept, which has emerged only lately. Lipids bind to single-span membrane proteins, both in the juxta-membrane region as well as in the hydrophobic membrane core. While some interactions counteract transmembrane helix oligomerization, in other cases lipid binding appears to enhance oligomerization. As reversible oligomerization is involved in activation of many membrane proteins, binding of defined lipids to single-span transmembrane proteins might be a mechanism to regulate and/or fine-tune the protein activity. But how could lipid binding trigger the activity of a protein? How can binding of a single lipid molecule to a transmembrane helix affect the structure of a transmembrane helix oligomer, and consequently its signaling state? These questions are discussed in the present article based on recent results obtained with simple, single-span transmembrane proteins. This article is part of a Special Issue entitled: Lipid-protein interactions.

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Impact of Bilayer Lipid Composition on the Structure and Topology of the Transmembrane Amyloid Precursor C99 Protein

Cited by 53 publications

References 32 publications

Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein

Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein

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

Functional competition within a membrane: Lipid recognition vs. transmembrane helix oligomerization

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