scholarly journals Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning

2017 ◽  
Vol 19 (40) ◽  
pp. 27556-27569 ◽  
Author(s):  
Xuewei Dong ◽  
Yunxiang Sun ◽  
Guanghong Wei ◽  
Ruth Nussinov ◽  
Buyong Ma
Keyword(s):  
Lipid Bilayer ◽  
Structural Stability ◽  
Salt Bridges ◽  
Membrane Interactions ◽  
Aβ Oligomers ◽  
Membrane Perturbation ◽  
Β Sheets ◽  
Membrane Thinning

Aβ–membrane interactions enhance structural stability of protofibrillar Aβ oligomers by stabilizing β-sheets and D23–K28 salt-bridges, and cause membrane perturbation by decreasing membrane's local thickness.

scholarly journals Structural Mechanism for Regulation of Bcl-2 protein Noxa by phosphorylation

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Christine B. Karim ◽  
L. Michel Espinoza-Fonseca ◽  
Zachary M. James ◽  
Eric A. Hanse ◽  
Jeffrey S. Gaynes ◽  
...  
Keyword(s):  
Md Simulations ◽  
Salt Bridges ◽  
Binding Assays ◽  
Peptide Backbone ◽  
Structural Mechanism ◽  
Binding Partner ◽  
Flexible Loop ◽  
Bh3 Domain ◽  
N Terminus ◽  
Β Sheets

Abstract We showed previously that phosphorylation of Noxa, a 54-residue Bcl-2 protein, at serine 13 (Ser13) inhibited its ability to promote apoptosis through interactions with canonical binding partner, Mcl-1. Using EPR spectroscopy, molecular dynamics (MD) simulations and binding assays, we offer evidence that a structural alteration caused by phosphorylation partially masks Noxa’s BH3 domain, inhibiting the Noxa-Mcl-1 interaction. EPR of unphosphorylated Noxa, with spin-labeled amino acid TOAC incorporated within the BH3 domain, revealed equilibrium between ordered and dynamically disordered states. Mcl-1 further restricted the ordered component for non-phosphorylated Noxa, but left the pSer13 Noxa profile unchanged. Microsecond MD simulations indicated that the BH3 domain of unphosphorylated Noxa is housed within a flexible loop connecting two antiparallel β-sheets, flanked by disordered N- and C-termini and Ser13 phosphorylation creates a network of salt-bridges that facilitate the interaction between the N-terminus and the BH3 domain. EPR showed that a spin label inserted near the N-terminus was weakly immobilized in unphosphorylated Noxa, consistent with a solvent-exposed helix/loop, but strongly constrained in pSer13 Noxa, indicating a more ordered peptide backbone, as predicted by MD simulations. Together these studies reveal a novel mechanism by which phosphorylation of a distal serine inhibits a pro-apoptotic BH3 domain and promotes cell survival.

scholarly journals Benzophenone Photoreactivity in a Lipid Bilayer To Probe Peptide/Membrane Interactions: Simple System, Complex Information

2019 ◽  
Vol 91 (14) ◽  
pp. 9102-9110
Author(s):  
Leïla Bechtella ◽  
Carla Kirschbaum ◽  
Marine Cosset ◽  
Gilles Clodic ◽  
Lucrèce Matheron ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Simple System ◽  
Membrane Interactions ◽  
Complex Information

scholarly journals Conversion between parallel and antiparallel β-sheets in wild-type and Iowa mutant fibrils

2017 ◽  
Author(s):  
Wenhui Xi ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Replica Exchange ◽  
Mutant Form ◽  
Salt Bridges ◽  
Wild Type ◽  
Β Sheets

AbstractUsing a variant of Hamilton-Replica-Exchange we study for wild type and Iowa mutant Aβ40 the conversion between fibrils with antiparallel β-sheets, and such with parallel β-sheets. We show that wild type and mutant form distinct salt bridges that in turn stabilize different fibril organizations. The conversion between the two fibril forms leads to the release of small aggregates that in the Iowa mutant may shift the equilibrium from fibrils to more toxic oligomers.

scholarly journals Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides

2017 ◽  
Vol 114 (43) ◽  
pp. E8977-E8986 ◽  
Author(s):  
Yosuke Senju ◽  
Maria Kalimeri ◽  
Essi V. Koskela ◽  
Pentti Somerharju ◽  
Hongxia Zhao ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Lipid Bilayer ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Lateral Diffusion ◽  
Lipid Binding ◽  
Actin Binding ◽  
Membrane Interactions ◽  
Dynamics Simulations

The actin cytoskeleton powers membrane deformation during many cellular processes, such as migration, morphogenesis, and endocytosis. Membrane phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], regulate the activities of many actin-binding proteins (ABPs), including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin, but the underlying molecular mechanisms have remained elusive. Moreover, because of a lack of available methodology, the dynamics of membrane interactions have not been experimentally determined for any ABP. Here, we applied a combination of biochemical assays, photobleaching/activation approaches, and atomistic molecular dynamics simulations to uncover the molecular principles by which ABPs interact with phosphoinositide-rich membranes. We show that, despite using different domains for lipid binding, these proteins associate with membranes through similar multivalent electrostatic interactions, without specific binding pockets or penetration into the lipid bilayer. Strikingly, our experiments reveal that these proteins display enormous differences in the dynamics of membrane interactions and in the ranges of phosphoinositide densities that they sense. Profilin and cofilin display transient, low-affinity interactions with phosphoinositide-rich membranes, whereas F-actin assembly factors Dia2 and N-WASP reside on phosphoinositide-rich membranes for longer periods to perform their functions. Ezrin and moesin, which link the actin cytoskeleton to the plasma membrane, bind membranes with very high affinity and slow dissociation dynamics. Unlike profilin, cofilin, Dia2, and N-WASP, they do not require high “stimulus-responsive” phosphoinositide density for membrane binding. Moreover, ezrin can limit the lateral diffusion of PI(4,5)P2 along the lipid bilayer. Together, these findings demonstrate that membrane-interaction mechanisms of ABPs evolved to precisely fulfill their specific functions in cytoskeletal dynamics.

The inhibitory mechanism of a fullerene derivative against amyloid-β peptide aggregation: an atomistic simulation study

2016 ◽  
Vol 18 (18) ◽  
pp. 12582-12591 ◽  
Author(s):  
Yunxiang Sun ◽  
Zhenyu Qian ◽  
Guanghong Wei
Keyword(s):  
Simulation Study ◽  
Atomistic Simulation ◽  
Amyloid Β ◽  
Fullerene Derivative ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Inhibitory Mechanism ◽  
Aβ Oligomers ◽  
Β Sheets

Fullerene inhibits the formation of inter-peptide β-sheets and β-hairpin motifs of toxic Aβ oligomers by binding to F4, Y10, L17–A21 and I31–V40 residues.

scholarly journals Visualization of lipid bilayer in the crystals by solvent contrast modulation

2014 ◽  
Vol 70 (a1) ◽  
pp. C1498-C1498
Author(s):  
Yoshiyuki Norimatsu ◽  
Junko Tsueda ◽  
Ayami Hirata ◽  
Shiho Iwasawa ◽  
Chikashi Toyoshima
Keyword(s):  
Lipid Bilayer ◽  
Electron Density ◽  
Lipid Bilayers ◽  
Transmembrane Helix ◽  
Real Space ◽  
New Method ◽  
Imaging Plate ◽  
Salt Bridges ◽  
Transmembrane Helices ◽  
X Ray

A new method of X-ray solvent contrast modulation was developed to visualize lipid bilayers in crystals of membrane proteins at a high enough resolution to resolve individual phospholipids molecules (~3.5 Å ). Visualization of lipid bilayer has been escaping from conventional crystallographic methods due to its extreme flexibility, and our knowledge on the behavior of lipid bilayer is still very much limited. Here we applied the new method of X-ray solvent contrast modulation to crystals of Ca2+-ATPase in 4 different physiological states. As phospholipids have to be added to make crystals of Ca2+-ATPase, it is expected that lipid bilayers are present in the crystals. Moreover, transmembrane helices of Ca2+-ATPase rearrange drastically during the reaction cycle and some of them show substantial movements perpendicular to the bilayer plane. Thus these crystals provide a rare opportunity to directly visualize phospholipids interacting with a membrane protein in different conformations. Complete diffraction data covering from 200 to 3.2 Å resolution were collected at BL41XU, Spring-8, using an R-Axis V imaging plate detector for crystals soaked in solvent of different electron density. A new concept "solvent exchange probability", which should be 1 in the bulk solvent, 0 inside the protein and an intermediate at interface, was introduced and used as a restraint for real space phase improvement. The electron density maps thus obtained clearly show that: (i) Phospholipid molecules surrounding the protein are fixed apparently by Arg/Lys-phosphate salt bridges or Trp-carbonyl hydrogen bonds and follow the movements of transmembrane helices. Movements of as large as 12 Å are allowed. (ii) If the movement of a transmembrane helix exceeds this limit, associated phospholipids change the partners for fixation or change the orientation of the entire protein molecule.

scholarly journals CryoEM structures of membrane pore and prepore complex reveal cytolytic mechanism of Pneumolysin

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Katharina van Pee ◽  
Alexander Neuhaus ◽  
Edoardo D'Imprima ◽  
Deryck J Mills ◽  
Werner Kühlbrandt ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lipid Bilayer ◽  
Virulence Factor ◽  
Pathogenic Bacteria ◽  
Soluble Form ◽  
Salt Bridges ◽  
Membrane Pore ◽  
X Ray ◽  
Target Membrane ◽  
Domain 3

Many pathogenic bacteria produce pore-forming toxins to attack and kill human cells. We have determined the 4.5 Å structure of the ~2.2 MDa pore complex of pneumolysin, the main virulence factor of Streptococcus pneumoniae, by cryoEM. The pneumolysin pore is a 400 Å ring of 42 membrane-inserted monomers. Domain 3 of the soluble toxin refolds into two ~85 Å β-hairpins that traverse the lipid bilayer and assemble into a 168-strand β-barrel. The pore complex is stabilized by salt bridges between β-hairpins of adjacent subunits and an internal α-barrel. The apolar outer barrel surface with large sidechains is immersed in the lipid bilayer, while the inner barrel surface is highly charged. Comparison of the cryoEM pore complex to the prepore structure obtained by electron cryo-tomography and the x-ray structure of the soluble form reveals the detailed mechanisms by which the toxin monomers insert into the lipid bilayer to perforate the target membrane.

scholarly journals Synthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

2018 ◽  
Author(s):  
Chris Dockendorff ◽  
Disha M. Gandhi ◽  
Ian H. Kimball ◽  
Kenneth S. Eum ◽  
Radda Rusinova ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Lipid Bilayers ◽  
Medicinal Chemistry ◽  
K Channel ◽  
Channel Activity ◽  
Synthetic Analogs ◽  
Voltage Gated ◽  
Protein Ligand Interactions ◽  
Membrane Perturbation ◽  
Ligand Interactions

Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogs and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.

Sign in / Sign up

Export Citation Format

Share Document