scholarly journals Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation

QRB Discovery ◽  
2020 ◽  
Vol 1 ◽  
Author(s):  
Ricardo Gaspar ◽  
Mikael Lund ◽  
Emma Sparr ◽  
Sara Linse
Keyword(s):  
Ionic Strength ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Lipid Vesicles ◽  
Intrinsically Disordered ◽  
Catalytic Surfaces ◽  
Disordered Protein ◽  
Salt Dependence ◽  
Fluorescence Measurements ◽  
The One

Abstractα-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson’s disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such interactions were confirmed in Monte Carlo simulations of α-syn monomers interacting with surface-grafted C-terminal tails, and found to be weakened in the presence of salt. Thus, nucleation of α-syn aggregation depends critically on an attractive electrostatic component that is screened by salt to the extent that it outweighs the screening of the long-range repulsion between negatively charged monomers and negative surfaces. Interactions between the positively charged N-termini of α-syn monomers on the one hand, and the negatively C-termini of α-syn on fibrils or vesicles surfaces on the other hand, are thus critical for nucleation.

Effects of flexibility and electrostatic interactions on the coupled binding–folding mechanisms of Chz.core and H2A.z–H2B

2017 ◽  
Vol 13 (10) ◽  
pp. 2152-2159 ◽  
Author(s):  
Xu Shang ◽  
Wenting Chu ◽  
Xiakun Chu ◽  
Chuanbo Liu ◽  
Liufang Xu ◽  
...  
Keyword(s):  
Free Energy ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Histone Variant ◽  
Energy Landscapes ◽  
Binding Mechanism ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Binding Preference ◽  
Free Energy Landscapes

The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. The coupled folding–binding mechanism of the complex can be quantified by the free energy landscapes.

scholarly journals α-carboxysome formation is mediated by the multivalent and disordered protein CsoS2

2019 ◽  
Author(s):  
Luke M. Oltrogge ◽  
Thawatchai Chaijarasphong ◽  
Allen W. Chen ◽  
Eric R. Bolin ◽  
Susan Marqusee ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Peptide Sequence ◽  
Protein Protein Interactions ◽  
X Ray ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
High Concentrations ◽  
Insight Into

AbstractCarboxysomes are bacterial microcompartments that function as the centerpiece of the bacterial CO2-concentrating mechanism, feeding high concentrations of CO2 to the enzyme Rubisco for fixation. The carboxysome self-assembles from thousands of individual proteins into icosahedral-like particles with a dense enzyme cargo encapsulated within a proteinaceous shell. In the case of the α-carboxysome, there is little molecular insight into protein-protein interactions which drive the assembly process. Here we show that the N-terminus of CsoS2, an intrinsically disordered protein found in the α-carboxysome, possesses a repeated peptide sequence that binds Rubisco. X-ray structural analysis of the peptide bound to Rubisco reveals a series of conserved electrostatic interactions that are only made with properly assembled hexadecameric Rubisco. Although biophysical measurements indicate this single interaction is weak, its implicit multivalency induces high-affinity binding through avidity. Taken together, our results indicate CsoS2 acts as an interaction hub to condense Rubisco and enable efficient α-carboxysome formation.

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

2018 ◽  
Author(s):  
Sarah Klass ◽  
Matthew J. Smith ◽  
Tahoe Fiala ◽  
Jessica Lee ◽  
Anthony Omole ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fusion Proteins ◽  
Organic Molecules ◽  
Intrinsically Disordered Protein ◽  
Protein Domain ◽  
Enzymatic Cleavage ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Self Assembling ◽  
Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.

scholarly journals Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 381
Author(s):  
Bálint Mészáros ◽  
Borbála Hajdu-Soltész ◽  
András Zeke ◽  
Zsuzsanna Dosztányi
Keyword(s):  
Gene Expression Regulation ◽  
Treatment Options ◽  
Intrinsically Disordered Protein ◽  
System Level ◽  
Alternative Mechanism ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Cancer Types ◽  
Cancer Drivers

Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.

scholarly journals Mediator subunit Med15 dictates the conserved “fuzzy” binding mechanism of yeast transcription activators Gal4 and Gcn4

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lisa M. Tuttle ◽  
Derek Pacheco ◽  
Linda Warfield ◽  
Damien B. Wilburn ◽  
Steven Hahn ◽  
...  
Keyword(s):  
Intrinsically Disordered Protein ◽  
Activation Function ◽  
Binding Mechanism ◽  
Binding Partner ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Independent Mechanism ◽  
Transcription Activators ◽  
Common Sequence

AbstractThe acidic activation domain (AD) of yeast transcription factor Gal4 plays a dual role in transcription repression and activation through binding to Gal80 repressor and Mediator subunit Med15. The activation function of Gal4 arises from two hydrophobic regions within the 40-residue AD. We show by NMR that each AD region binds the Mediator subunit Med15 using a “fuzzy” protein interface. Remarkably, comparison of chemical shift perturbations shows that Gal4 and Gcn4, two intrinsically disordered ADs of different sequence, interact nearly identically with Med15. The finding that two ADs of different sequence use an identical fuzzy binding mechanism shows a common sequence-independent mechanism for AD-Mediator binding, similar to interactions within a hydrophobic cloud. In contrast, the same region of Gal4 AD interacts strongly with Gal80 via a distinct structured complex, implying that the structured binding partner of an intrinsically disordered protein dictates the type of protein–protein interaction.

scholarly journals Biomorphs: Complex Morphogenesis by a Model Intrinsically Disordered Protein (Small 51/2020)

Small ◽  
2020 ◽  
Vol 16 (51) ◽  
pp. 2070276
Author(s):  
Constancio González‐Obeso ◽  
Miguel González‐Pérez ◽  
João F. Mano ◽  
Matilde Alonso ◽  
José Carlos Rodríguez‐Cabello
Keyword(s):  
Intrinsically Disordered Protein ◽  
Intrinsically Disordered ◽  
Disordered Protein
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