scholarly journals Effective concentrations enforced by intrinsically disordered linkers are governed by polymer physics

2019 ◽  
Author(s):  
Charlotte S. Sørensen ◽  
Magnus Kjaergaard
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Polymer Physics ◽  
Disordered Proteins ◽  
Multidomain Proteins ◽  
Fluorescent Biosensor ◽  
Intrinsically Disordered ◽  
Theoretical Predictions ◽  
Quantitative Understanding ◽  
The Individual ◽  
The Relationship

AbstractMany multidomain proteins contain disordered linkers that regulate inter-domain contacts, and thus the effective concentrations that govern intra-molecular reactions. Effective concentrations are rarely measured experimentally and therefore little is known about how they relate to linker architecture. We have directly measured the effective concentrations enforced by disordered protein linkers using a new fluorescent biosensor. We show that effective concentrations follow simple geometric models based on polymer physics, offering an indirect method to probe the structural properties of the linker. The compaction of the disordered linker depends not only on net charge, but also on the type of charged residues. In contrast to theoretical predictions, we found that polyampholyte linkers can contract to similar dimensions as globular proteins. Hydrophobicity has little effect in itself, but aromatic residues lead to strong compaction likely through π-interactions. Finally, we find that the individual contributors to chain compaction are not additive. This work represents perhaps the most systematic study of the relationship between sequence and structure of intrinsically disordered proteins so far. A quantitative understanding of the relationship between effective concentration and linker sequence will be crucial for understanding disorder-based allosteric regulation in multidomain proteins.

scholarly journals Effective concentrations enforced by intrinsically disordered linkers are governed by polymer physics

2019 ◽  
Vol 116 (46) ◽  
pp. 23124-23131 ◽  
Author(s):  
Charlotte S. Sørensen ◽  
Magnus Kjaergaard
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Polymer Physics ◽  
Disordered Proteins ◽  
Multidomain Proteins ◽  
Fluorescent Biosensor ◽  
Intrinsically Disordered ◽  
Theoretical Predictions ◽  
Quantitative Understanding ◽  
The Individual ◽  
The Relationship

Many multidomain proteins contain disordered linkers that regulate interdomain contacts, and thus the effective concentrations that govern intramolecular reactions. Effective concentrations are rarely measured experimentally, and therefore little is known about how they relate to linker architecture. We have directly measured the effective concentrations enforced by disordered protein linkers using a fluorescent biosensor. We show that effective concentrations follow simple geometric models based on polymer physics, offering an indirect method to probe the structural properties of the linker. The compaction of the disordered linker depends not only on net charge, but also on the type of charged residues. In contrast to theoretical predictions, we found that polyampholyte linkers can contract to similar dimensions as globular proteins. Hydrophobicity has little effect in itself, but aromatic residues lead to strong compaction, likely through π-interactions. Finally, we find that the individual contributors to chain compaction are not additive. We thus demonstrate that direct measurement of effective concentrations can be used in systematic studies of the relationship between sequence and structure of intrinsically disordered proteins. A quantitative understanding of the relationship between effective concentration and linker sequence will be crucial for understanding disorder-based allosteric regulation in multidomain proteins.

scholarly journals Charge fluctuation effects on the shape of flexible polyampholytes with applications to Intrinsically disordered proteins

2018 ◽  
Author(s):  
Himadri S. Samanta ◽  
Debayan Chakraborty ◽  
D. Thirumalai
Keyword(s):  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Debye Length ◽  
Disordered Proteins ◽  
Radius Of Gyration ◽  
Charge Fluctuation ◽  
Net Charge ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Theoretical Predictions

Random polyampholytes (PAs) contain positively and negatively charged monomers that are distributed randomly along the polymer chain. The interaction between charges is assumed to be given by the Debye-Huckel potential. We show that the size of the PA is determined by an interplay between electrostatic interactions, giving rise to the polyelectrolyte (PE) effect due to net charge per monomer (σ), and an effective attractive PA interaction due to charge fluctuations, δσ. The interplay between these terms gives rise to non-monotonic dependence of the radius of gyration, Rg on the inverse Debye length, κ when PA effects are important . In the opposite limit, Rg decreases monotonically with increasing κ. Simulations of PA chains, using a charged bead-spring model, further corroborates our theoretical predictions. The simulations unambiguously show that conformational heterogeneity manifests itself among sequences that have identical PA parameters. A clear implication is that the phases of PA sequences, and by inference IDPs, cannot be determined using only the bare PA parameters (σ and δσ).The theory is used to calculate the changes in Rg on N, the number of residues for a set of Intrinsically Disordered Proteins (IDPs). For a certain class of IDPs, with N between 24 to 441, the size grows as Rg ~ N0.6, which agrees with data from Small Angle X-ray Scattering (SAXS) experiments.

scholarly journals The disordered boundary of the cell: emerging properties of membrane-bound intrinsically disordered proteins

2019 ◽  
Vol 10 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Irrem-Laareb Mohammad ◽  
Borja Mateos ◽  
Miquel Pons
Keyword(s):  
Lipid Bilayers ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
High Concentrations ◽  
The Individual ◽  
Confined Environment

AbstractWe define the disordered boundary of the cell (DBC) as the system formed by membrane tethered intrinsically disordered protein regions, dynamically coupled to the underlying membrane.The emerging properties of the DBC makes it a global system of study, which cannot be understood from the individual properties of their components. Similarly, the properties of lipid bilayers cannot be understood from just the sum of the properties of individual lipid molecules.The highly anisotropic confined environment, restricting the position and orientation of interacting sites, is affecting the properties of individual disordered proteins. In fact, the collective effect caused by high concentrations of disordered proteins extend beyond the sum of individual effects.Examples of emerging properties of the DBC include enhanced protein-protein interactions, protein-driven phase separations, Z-compartmentalization, and protein modulated electrostatics.

scholarly journals Single Molecule FRET: A Powerful Tool to Study Intrinsically Disordered Proteins

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 140 ◽  
Author(s):  
Sharonda LeBlanc ◽  
Prakash Kulkarni ◽  
Keith Weninger
Keyword(s):  
Single Molecule ◽  
Biological Networks ◽  
Intrinsically Disordered Proteins ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Polymer Physics ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Single Molecule Fret ◽  
Random Fluctuations

Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single molecule fluorescence (or Förster) resonance energy transfer (smFRET) is one of the few approaches that are sensitive to transient populations of sub-states within molecular ensembles. In some implementations, smFRET has sufficient time resolution to resolve transitions in IDP behaviors. Here we present experimental issues to consider when applying smFRET to study IDP configuration. We illustrate the power of applying smFRET to IDPs by discussing two cases in the literature of protein systems for which smFRET has successfully reported phosphorylation-induced modification (but not elimination) of the disordered properties that have been connected to impacts on the related biological function. The examples we discuss, PAGE4 and a disordered segment of the GluN2B subunit of the NMDA receptor, illustrate the great potential of smFRET to inform how IDP function can be regulated by controlling the detailed ensemble of disordered states within biological networks.

scholarly journals Single-molecule spectroscopy of unfolded proteins and chaperonin action

2014 ◽  
Vol 395 (7-8) ◽  
pp. 689-698 ◽  
Author(s):  
Hagen Hofmann
Keyword(s):  
Single Molecule ◽  
Molecular Chaperones ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Unfolded Proteins ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Cellular Environment ◽  
Quantitative Understanding ◽  
Polypeptide Chains

Abstract In the past decade, single-molecule fluorescence techniques provided important insights into the structure and dynamics of proteins. In particular, our understanding of the heterogeneous conformational ensembles of unfolded and intrinsically disordered proteins (IDPs) improved substantially by a combination of FRET-based single-molecule techniques with concepts from polymer physics. A complete knowledge of the forces that act in unfolded polypeptide chains will not only be important to understand the initial steps of protein folding reactions, but it will also be crucial to rationalize the coupling between ligand-binding and folding of IDPs, and the interaction of denatured proteins with molecular chaperones in the crowded cellular environment. Here, I give a personalized review of some of the key findings from my own research that contributed to a more quantitative understanding of unfolded proteins and their interactions with molecular chaperones.

scholarly journals Describing sequence–ensemble relationships for intrinsically disordered proteins

2012 ◽  
Vol 449 (2) ◽  
pp. 307-318 ◽  
Author(s):  
Albert H. Mao ◽  
Nicholas Lyle ◽  
Rohit V. Pappu
Keyword(s):  
First Principles ◽  
Intrinsically Disordered Proteins ◽  
Polymer Physics ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Protein Nucleic Acid ◽  
Cellular Phenotypes ◽  
Nucleic Acid Interactions ◽  
And Control ◽  
Functional Mechanisms

Intrinsically disordered proteins participate in important protein–protein and protein–nucleic acid interactions and control cellular phenotypes through their prominence as dynamic organizers of transcriptional, post-transcriptional and signalling networks. These proteins challenge the tenets of the structure–function paradigm and their functional mechanisms remain a mystery given that they fail to fold autonomously into specific structures. Solving this mystery requires a first principles understanding of the quantitative relationships between information encoded in the sequences of disordered proteins and the ensemble of conformations they sample. Advances in quantifying sequence–ensemble relationships have been facilitated through a four-way synergy between bioinformatics, biophysical experiments, computer simulations and polymer physics theories. In the present review we evaluate these advances and the resultant insights that allow us to develop a concise quantitative framework for describing the sequence–ensemble relationships of intrinsically disordered proteins.

scholarly journals αα-hub domains and intrinsically disordered proteins – a decisive combo

2020 ◽  
pp. jbc.REV120.012928
Author(s):  
Katrine Bugge ◽  
Lasse Staby ◽  
Edoardo Salladini ◽  
Rasmus G. Falbe-Hansen ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
New Concepts ◽  
Protein Protein Interaction Networks ◽  
Living Organisms ◽  
The Individual ◽  
New Research

Hub proteins are central nodes in protein–protein interaction networks with critical importance to all living organisms. Recently, a new group of folded hub domains, the αα-hubs, was defined based on a shared αα-hairpin super-secondary structural foundation. The members PAH, RST, TAFH, NCBD and HHD are found in large proteins such as Sin3, RCD1, TAF4, CBP and harmonin, which organize disordered transcriptional regulators and membrane scaffolds in interactomes of importance to human diseases and plant quality. In this review, studies of structures, functions, and complexes across the αα-hubs are described and compared to provide a unified description of the group. This analysis expands the associated molecular concepts of “one domain – one superbinding site”, motif-based ligand binding, and coupled folding and binding of intrinsically disordered ligands to additional concepts of importance to signal fidelity. These include context, motif reversibility, multivalency, complex heterogeneity, synergistic αα-hub:ligand folding, accessory binding-sites, and supramodules. We propose that these multifaceted protein–protein interaction properties are made possible by the characteristics of the αα-hub fold, including super-site properties, dynamics, variable topologies, accessory helices and malleability and abetted by adaptability of the disordered ligands. Critically, these features provide additional filters for specificity. With the presentations of new concepts, this review opens for new research questions addressing properties across the group, which are driven from concepts discovered in studies of the individual members. Combined, the members of the αα-hubs are ideal models for deconvoluting signal fidelity maintained by folded hubs and their interactions with intrinsically disordered ligands.

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