Structural Heterogeneity in Transmembrane Amyloid Precursor Protein Homodimer Is a Consequence of Environmental Selection

Domı́nguez, Laura; Foster, Leigh; Meredith, Stephen C.; Straub, John E.; Thirumalai, D.

doi:10.1021/ja503150x

Cited by 43 publications

(65 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

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.

Self Cite

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%

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.

Self Cite

116

View full text Add to dashboard Cite

show abstract

“…In addition, MD simulations have revealed subtle differences in the ligand-bound conformations of the ECD (Sanders et al, 2013), and domain II has recently been identified as a potential mediator of subtle differences in ligand binding and specific receptor states (Bessman et al, 2014). Further, mutations in the JM-A region alter the energetics of ligand binding to the ECD (Macdonald-Obermann and Pike, 2009), and there is clear evidence that the active conformation of the EGFR TM is flexible and capable of adopting multiple conformation (Endres et al, 2013), like other single pass TM domains (Dominguez et al, 2014). Taken together, these observations support a model in which different ligand-dependent JM-A conformations result from three distinct ligand-bound ECD conformations that are transmitted faithfully through the membrane-sequestered TM helical dimer.…”

Section: Discussionmentioning

confidence: 99%

Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region

Doerner

Scheck

Schepartz

2015

Chemistry & Biology

View full text Add to dashboard Cite

Summary Binding of the growth factor TGF-α to the EGFR extracellular domain is encoded through the formation of a unique anti-parallel coiled coil within the juxtamembrane segment. This new coiled coil is an ‘inside-out’ version of the coiled coil formed in the presence of EGF. A third, intermediary coiled coil interface is formed in the juxtamembrane segment when EGFR is stimulated with betacellulin. The seven growth factors that activate EGFR in mammalian systems (EGF, TGF-α, epigen, epiregulin, betacellulin, heparin-binding EGF, and amphiregulin) fall into distinct categories in which the structure of the coiled coil induced within the juxtamembrane segment correlates with cell state. The observation that coiled coil state tracks with the downstream signaling profiles for each ligand provides evidence for growth factor functional selectivity by EGFR. Encoding growth factor identity in alternative coiled coil rotamers provides a simple and elegant method for communicating chemical information across the plasma membrane.

show abstract

“…In another study a multiscale approach employing coarse-grained MARTINI followed by all-atom MD simulations allowed the identification of the homodimer structure of two C-terminal fragments of amyloid precursor protein (C99) in the POPC bilayer and the DPC micelle. 570 Carpenter and co-workers performed coarse-grained MD simulation of the tetramerization of four transmembrane helices forming the transmembrane domain of influenza A M2 channel protein. 571 Comparison with the X-ray and NMR structures of the M2 bundle suggests that the resulting model may correspond to a closed state of the channel.…”

Section: Membrane Proteinsmentioning

confidence: 99%

Coarse-Grained Protein Models and Their Applications

et al. 2016

View full text Add to dashboard Cite

The traditional computational modeling of protein structure, dynamics, and interactions remains difficult for many protein systems. It is mostly due to the size of protein conformational spaces and required simulation time scales that are still too large to be studied in atomistic detail. Lowering the level of protein representation from all-atom to coarse-grained opens up new possibilities for studying protein systems. In this review we provide an overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics, and interactions. A more detailed description is given for applications of coarse-grained models suitable for efficient combinations with all-atom simulations in multiscale modeling strategies.

show abstract

Structural Heterogeneity in Transmembrane Amyloid Precursor Protein Homodimer Is a Consequence of Environmental Selection

Cited by 43 publications

References 59 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

Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region

Coarse-Grained Protein Models and Their Applications

Contact Info

Product

Resources

About