Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment

Nadezhdin, Kirill D.; Bocharova, Olga V.; Bocharov, Eduard V.; Arseniev, Alexander S.

doi:10.1016/j.febslet.2012.04.062

Cited by 81 publications

(188 citation statements)

References 26 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…The proposed structure of GSQ-C99 15−55 in dodecyl-phosphocholine (DPC) is a X-like left-handed dimer stabilized through interactions involving an extended heptad repeat motif in the C-terminal TM helical region. In contrast, the structure of C99 28−55 homodimer in DPC micelle is a right-handed coiled-coil in agreement with our simulation results of C99 15−55 homodimer in DPC micelle (23,24). These studies raise critical questions related to the peptide environment, focusing on how factors such as micelle size and interfacial curvature might influence peptide structures (25,26).…”

supporting

confidence: 88%

“…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: 57%

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

supporting

confidence: 88%

Section: Discussionmentioning

confidence: 57%

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

“…6c) [225]. In this structure, two G 33 xxxG 38 motifs do not face each other, which contradict to the previous experiment and simulations.…”

Section: Recent Membrane and Membrane Protein Simulations Using Enmentioning

confidence: 61%

Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms

Mori

Miyashita²,

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

127

108

View full text Add to dashboard Cite

This paper reviews various enhanced conformational sampling methods and explicit/implicit solvent/membrane models, as well as their recent applications to the exploration of the structure and dynamics of membranes and membrane proteins. Molecular dynamics simulations have become an essential tool to investigate biological problems, and their success relies on proper molecular models together with efficient conformational sampling methods. The implicit representation of solvent/membrane environments is reasonable approximation to the explicit all-atom models, considering the balance between computational cost and simulation accuracy. Implicit models can be easily combined with replica-exchange molecular dynamics methods to explore a wider conformational space of a protein. Other molecular models and enhanced conformational sampling methods are also briefly discussed. As application examples, we introduce recent simulation studies of glycophorin A, phospholamban, amyloid precursor protein, and mixed lipid bilayers and discuss the accuracy and efficiency of each simulation model and method. This article is part of a Special Issue entitled: Membrane Proteins. Guest Editors: J.C. Gumbart and Sergei Noskov.

show abstract

“…58)), left-handed TM homodimers (PDB code: 2M0B, 2L9U 59 , 2K9Y 28 , 2LZL 27 , 2L34 (ref. 60), 2HAC 3 , 2L6W 61 and 2LOH 62 ), tetramers (PDB code: 3LBW M2A closed state 52 , 3BKD M2A open state 53 and 2KIX 63 ) and pentamer (PDB code: 2KYV 64 ). Modelled regions included both residues in the TM and residues in the water–lipid interface regions.…”

Section: Methodsmentioning

confidence: 99%

Evolutionary-guided de novo structure prediction of self-associated transmembrane helical proteins with near-atomic accuracy

Wang

Barth

2015

Nat Commun

View full text Add to dashboard Cite

How specific protein associations regulate the function of membrane receptors remains poorly understood. Conformational flexibility currently hinders the structure determination of several classes of membrane receptors and associated oligomers. Here we develop EFDOCK-TM, a general method to predict self-associated transmembrane protein helical (TMH) structures from sequence guided by co-evolutionary information. We show that accurate intermolecular contacts can be identified using a combination of protein sequence covariation and TMH binding surfaces predicted from sequence. When applied to diverse TMH oligomers, including receptors characterized in multiple conformational and functional states, the method reaches unprecedented near-atomic accuracy for most targets. Blind predictions of structurally uncharacterized receptor tyrosine kinase TMH oligomers provide a plausible hypothesis on the molecular mechanisms of disease-associated point mutations and binding surfaces for the rational design of selective inhibitors. The method sets the stage for uncovering novel determinants of molecular recognition and signalling in single-spanning eukaryotic membrane receptors.

show abstract

Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment

Cited by 81 publications

References 26 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

Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms

Evolutionary-guided de novo structure prediction of self-associated transmembrane helical proteins with near-atomic accuracy

Contact Info

Product

Resources

About