The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Michele F. M. Sciacca ◽  
Fabio Lolicato ◽  
Carmelo Tempra ◽  
Federica Scollo ◽  
Bikash R. Sahoo ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Intrinsically Disordered ◽  
Molecular Events ◽  
Membrane Poration ◽  
Synuclein Proteins

<p>Increasing number of human diseases have been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer’s, and Parkinson’s, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.<b></b></p>

scholarly journals The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Michele F. M. Sciacca ◽  
Fabio Lolicato ◽  
Carmelo Tempra ◽  
Federica Scollo ◽  
Bikash R. Sahoo ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Intrinsically Disordered ◽  
Molecular Events ◽  
Membrane Poration ◽  
Synuclein Proteins

<p>Increasing number of human diseases have been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer’s, and Parkinson’s, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.<b></b></p>

scholarly journals Connecting the αα-hubs: same fold, disordered ligands, new functions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lasse Staby ◽  
Katrine Bugge ◽  
Rasmus Greve Falbe-Hansen ◽  
Edoardo Salladini ◽  
Karen Skriver ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Telomere Elongation ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Functional Understanding ◽  
Signal Specificity ◽  
Telomere Regulation ◽  
Secondary Structure Motif

Abstract Background Signal fidelity depends on protein–protein interaction–‘hubs’ integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators. Methods Comparative structural biology. Results We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk. Conclusion The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.

scholarly journals Planar Boronic Graphene and Nitrogenized Graphene Heterostructure for Protein Stretch and Confinement

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1756
Author(s):  
Xuchang Su ◽  
Zhi He ◽  
Lijun Meng ◽  
Hong Liang ◽  
Ruhong Zhou
Keyword(s):  
Single Molecule ◽  
Intrinsically Disordered Proteins ◽  
Electron Tunneling ◽  
Amyloid Β ◽  
Protein Sequencing ◽  
Disordered Proteins ◽  
Force Microscopy ◽  
Intrinsically Disordered ◽  
Atomic Force ◽  
Dynamics Simulations

Single-molecule techniques such as electron tunneling and atomic force microscopy have attracted growing interests in protein sequencing. For these methods, it is critical to refine and stabilize the protein sample to a “suitable mode” before applying a high-fidelity measurement. Here, we show that a planar heterostructure comprising boronic graphene (BC3) and nitrogenized graphene (C3N) sandwiched stripe (BC3/C3N/BC3) is capable of the effective stretching and confinement of three types of intrinsically disordered proteins (IDPs), including amyloid-β (1–42), polyglutamine (Q42), and α-Synuclein (61–95). Our molecular dynamics simulations demonstrate that the protein molecules interact more strongly with the C3N stripe than the BC3 one, which leads to their capture, elongation, and confinement along the center C3N stripe of the heterostructure. The conformational fluctuations of IDPs are substantially reduced after being stretched. This design may serve as a platform for single-molecule protein analysis with reduced thermal noise.

scholarly journals Progressive Phosphorylation Modulates the Self-Association of a Variably Modified Histone H3 Peptide

2021 ◽  
Vol 8 ◽  
Author(s):  
George V. Papamokos ◽  
George Tziatzos ◽  
Dimitrios G. Papageorgiou ◽  
Spyros Georgatos ◽  
Efthimios Kaxiras ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Histone H3 ◽  
Intramolecular Interactions ◽  
Disordered Proteins ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Self Association ◽  
Dynamics Simulations ◽  
Peptide Charge

Protein phosphorylation is a key regulatory mechanism in eukaryotic cells. In the intrinsically disordered histone tails, phosphorylation is often a part of combinatorial post-translational modifications and an integral part of the “histone code” that regulates gene expression. Here, we study the association between two histone H3 tail peptides modified to different degrees, using fully atomistic molecular dynamics simulations. Assuming that the initial conformations are either α-helical or fully extended, we compare the propensity of the two peptides to associate with one another when both are unmodified, one modified and the other unmodified, or both modified. The simulations lead to the identification of distinct inter- and intramolecular interactions in the peptide dimer, highlighting a prominent role of a fine-tuned phosphorylation rheostat in peptide association. Progressive phosphorylation appears to modulate peptide charge, inducing strong and specific intermolecular interactions between the monomers, which do not result in the formation of amorphous or ordered aggregates, as documented by experimental evidence derived from Circular Dichroism and NMR spectroscopy. However, upon complete saturation of positive charges by phosphate groups, this effect is reversed: intramolecular interactions prevail and dimerization of zero-charge peptides is markedly reduced. These findings underscore the role of phosphorylation thresholds in the dynamics of intrinsically disordered proteins. Phosphorylation rheostats might account for the divergent effects of histone modifications on the modulation of chromatin structure.

scholarly journals Examining the Ensembles of Amyloid-β Monomer Variants and their Propensities to Form Fibers Using an Energy Landscape Visualization Method

2021 ◽  
Author(s):  
Murilo N Sanches ◽  
Kaitlin Knapp ◽  
Antonio Bento Oliveira Junior ◽  
Peter G Wolynes ◽  
Jose N Onuchic ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Energy Landscape ◽  
Single Point ◽  
Point Mutations ◽  
Amyloid Β ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Visualization Method ◽  
Intrinsically Disordered ◽  
Single Point Mutations

The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ40 and Aβ42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer's disease (AD). Experiments have shown that even though the natural abundance of Aβ42 is smaller than that for Aβ40, the Aβ42 is more aggregation-prone compared to Aβ40. Moreover, several single-point mutations are associated with early-onset forms of AD. This work analyzes coarse-grained AWSEM simulations of normal Aβ40 and Aβ42 monomers, along with six single-point mutations associated with early on set disease. We analyzed the simulations using the Energy Landscape Visualization Method (ELViM), a reaction coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino-acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.

scholarly journals Unraveling the Mechanism of Functional and Pathological Amyloid Formation from Intrinsically Disordered Proteins

2020 ◽  
Vol 118 (3) ◽  
pp. 59a
Author(s):  
Mily Bhattacharya ◽  
Anjali Giri ◽  
Jaspreet Kaur ◽  
Priyanka Dogra ◽  
Samrat Mukhopadhyay
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Intrinsically Disordered

scholarly journals Structural and Functional Dynamics of Dehydrins: A Plant Protector Protein under Abiotic Stress

2018 ◽  
Vol 19 (11) ◽  
pp. 3420 ◽  
Author(s):  
Zhengyang Yu ◽  
Xin Wang ◽  
Linsheng Zhang
Keyword(s):  
Abiotic Stress ◽  
Regulatory Networks ◽  
Intrinsically Disordered Proteins ◽  
Stress Factors ◽  
Disordered Proteins ◽  
Transcriptional Level ◽  
Gene Expressions ◽  
Intrinsically Disordered ◽  
Functional Dynamics

Abiotic stress affects the growth and development of crops tremendously, worldwide. To avoid adverse environmental effects, plants have evolved various efficient mechanisms to respond and adapt to harsh environmental factors. Stress conditions are associated with coordinated changes in gene expressions at a transcriptional level. Dehydrins have been extensively studied as protectors in plant cells, owing to their vital roles in sustaining the integrity of membranes and lactate dehydrogenase (LDH). Dehydrins are highly hydrophilic and thermostable intrinsically disordered proteins (IDPs), with at least one Lys-rich K-segment. Many dehydrins are induced by multiple stress factors, such as drought, salt, extreme temperatures, etc. This article reviews the role of dehydrins under abiotic stress, regulatory networks of dehydrin genes, and the physiological functions of dehydrins. Advances in our understanding of dehydrin structures, gene regulation and their close relationships with abiotic stresses demonstrates their remarkable ability to enhance stress tolerance in plants.

scholarly journals Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

2016 ◽  
Vol 18 (5) ◽  
pp. 704 ◽  
Author(s):  
StevenM Mooney ◽  
MohitKumar Jolly ◽  
Herbert Levine ◽  
Prakash Kulkarni
Keyword(s):  
Prostate Cancer ◽  
Phenotypic Plasticity ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals Affinity of IDPs to their targets is modulated by ion-specific changes in kinetics and residual structure

2017 ◽  
Vol 114 (37) ◽  
pp. 9882-9887 ◽  
Author(s):  
Basile I. M. Wicky ◽  
Sarah L. Shammas ◽  
Jane Clarke
Keyword(s):  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Marginal Stability ◽  
Residual Structure ◽  
Intrinsically Disordered ◽  
Folded Proteins ◽  
The Stability ◽  
Ion Profiles

Intrinsically disordered proteins (IDPs) are characterized by a lack of defined structure. Instead, they populate ensembles of rapidly interconverting conformations with marginal structural stabilities. Changes in solution conditions such as temperature and crowding agents consequently affect IDPs more than their folded counterparts. Here we reveal that the residual structure content of IDPs is modulated both by ionic strength and by the type of ions present in solution. We show that these ion-specific structural changes result in binding affinity shifts of up to sixfold, which happen through alteration of both association and dissociation rates. These effects follow the Hofmeister series, but unlike the well-established effects on the stability of folded proteins, they already occur at low, hypotonic concentrations of salt. We attribute this sensitivity to the marginal stability of IDPs, which could have physiological implications given the role of IDPs in signaling, the asymmetric ion profiles of different cellular compartments, and the role of ions in biology.

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