scholarly journals Effects of Sequence Composition and Patterning on the Structure and Dynamics of Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Andrei Vovk ◽  
Anton Zilman
Keyword(s):  
Amino Acid ◽  
Intrinsically Disordered Proteins ◽  
Amino Acid Sequences ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Radius Of Gyration ◽  
Sequence Composition ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Polymer Models

AbstractUnlike the well defined structures of classical natively folded proteins, Intrinsically Disordered Proteins (IDP) and Intrinsically Disordered Regions (IDR) dynamically span large conformational and structural ensembles. This dynamic disorder impedes the study of the relationship between the amino acid sequences of the IDPs and their spatial structures, dynamics, and function. Multiple experimental and theoretical evidence points in many cases to the overall importance of the general properties of the amino acid sequence of the IPDs rather than their precise atomistic details. However, while different experimental techniques can probe aspects of the IDP conformations, often different techniques or conditions offer seemingly contradictory results. Using coarse-grained polymer models informed by experimental observations, we investigate the effects of several key variables on the dimensions and the dynamics of IDPs. The coarse-grained simulations are in a good agreement with the results of atomistic MD. We show that the sequence composition and patterning are well reflected in the global conformational variables such as the radius of gyration and hydrodynamic radius, while the end-to-end distance and dynamics are highly sequence specific. We identify the conditions that allow mapping of highly heterogeneous sequences of IDPs onto averaged minimal polymer models. We discuss the implications of these results for the interpretation of the recent experimental measurements, and for further development of appropriate mesoscopic models of IDPs.

NOT THAT RIGID MIDGETS AND NOT SO FLEXIBLE GIANTS: ON THE ABUNDANCE AND ROLES OF INTRINSIC DISORDER IN SHORT AND LONG PROTEINS

2012 ◽  
Vol 20 (04) ◽  
pp. 471-511 ◽  
Author(s):  
MARK HOWELL ◽  
RYAN GREEN ◽  
ALEXIS KILLEEN ◽  
LAMAR WEDDERBURN ◽  
VINCENT PICASCIO ◽  
...  
Keyword(s):  
Amino Acid ◽  
Intrinsically Disordered Proteins ◽  
Biological Activities ◽  
Intrinsic Disorder ◽  
Amino Acid Sequences ◽  
Disordered Proteins ◽  
Biological Functions ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteins ◽  
Disordered Regions

Intrinsically disordered proteins or proteins with disordered regions are very common in nature. These proteins have numerous biological functions which are complementary to the biological activities of traditional ordered proteins. A noticeable difference in the amino acid sequences encoding long and short disordered regions was found and this difference was used in the development of length-dependent predictors of intrinsic disorder. In this study, we analyze the scaling of intrinsic disorder in eukaryotic proteins and investigate the presence of length-dependent functions attributed to proteins containing long disordered regions.

scholarly journals Ubiquitin-independent protein degradation in proteasomes

2018 ◽  
Vol 64 (2) ◽  
pp. 134-148 ◽  
Author(s):  
O.A. Buneeva ◽  
A.E. Medvedev
Keyword(s):  
Protein Degradation ◽  
Mammalian Cells ◽  
Intrinsically Disordered Proteins ◽  
Amino Acid Sequences ◽  
Disordered Proteins ◽  
20S Proteasome ◽  
Independent Manner ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Independent Protein

Proteasomes are large supramolecular protein complexes present in all prokaryotic and eukaryotic cells, where they perform targeted degradation of intracellular proteins. Until recently, it was generally accepted that prior proteolytic degradation in proteasomes the proteins had to be targeted by ubiquitination: the ATP-dependent addition of (typically four sequential) residues of the low-molecular ubiquitin protein, involving the ubiquitin-activating enzyme, ubiquitin-conjugating enzyme and ubiquitin ligase. The cytoplasm and nucleoplasm proteins labeled in this way are then digested in 26S proteasomes. However, in recent years it has become increasingly clear that using this route the cell eliminates only a part of unwanted proteins. Many proteins can be cleaved by the 20S proteasome in an ATP-independent manner and without previous ubiquitination. Ubiquitin-independent protein degradation in proteasomes is a relatively new area of studies of the role of the ubiquitin-proteasome system. However, recent data obtained in this direction already correct existing concepts about proteasomal degradation of proteins and its regulation. Ubiquitin-independent proteasome degradation needs the main structural precondition in proteins: the presence of unstructured regions in the amino acid sequences that provide interaction with the proteasome. Taking into consideration that in humans almost half of all genes encode proteins that contain a certain proportion of intrinsically disordered regions, it appears that the list of proteins undergoing ubiquitin-independent degradation will demonstrate further increase. Since 26S of proteasomes account for only 30% of the total proteasome content in mammalian cells, most of the proteasomes exist in the form of 20S complexes. The latter suggests that ubiquitin-independent proteolysis performed by the 20S proteasome is a natural process of removing damaged proteins from the cell and maintaining a constant level of intrinsically disordered proteins. In this case, the functional overload of proteasomes in aging and/or other types of pathological processes, if it is not accompanied by triggering more radical mechanisms for the elimination of damaged proteins, organelles and whole cells, has the most serious consequences for the whole organism.

scholarly journals Proteus: A Random Forest Classifier to Predict Disorder-to-Order Transitioning Binding Regions in Intrinsically Disordered Proteins

2016 ◽  
Author(s):  
Sankar Basu ◽  
Fredrik Söderquist ◽  
Björn Wallner
Keyword(s):  
Amino Acid ◽  
Random Forest ◽  
Amino Acid Sequence ◽  
Intrinsically Disordered Proteins ◽  
Random Forest Classifier ◽  
Amino Acid Sequences ◽  
Order Transition ◽  
Disordered Proteins ◽  
Data Set ◽  
Intrinsically Disordered

AbstractThe focus of the computational structural biology community has taken a dramatic shift over the past one-and-a-half decades from the classical protein structure prediction problem to the possible understanding of intrinsically disordered proteins (IDP) or proteins containing regions of disorder (IDPR). The current interest lies in the unraveling of a disorder-to-order transitioning code embedded in the amino acid sequences of IDPs / IDPRs. Disordered proteins are characterized by an enormous amount of structural plasticity which makes them promiscuous in binding to different partners, multi-functional in cellular activity and atypical in folding energy landscapes resembling partially folded molten globules. Also, their involvement in several deadly human diseases (e.g. cancer, cardiovascular and neurodegenerative diseases) makes them attractive drug targets, and important for a biochemical understanding of the disease(s). The study of the structural ensemble of IDPs is rather difficult, in particular for transient interactions. When bound to a structured partner, an IDPR adapts an ordered conformation in the complex. The residues that undergo this disorder-to-order transition are called protean residues, generally found in short contiguous stretches and the first step in understanding the modus operandi of an IDP / IDPR would be to predict these residues. There are a few available methods which predict these protean segments from their amino acid sequences; however, their performance reported in the literature leaves clear room for improvement. With this background, the current study presents 'Proteus', a random forest classifier that predicts the likelihood of a residue undergoing a disorder-to-order transition upon binding to a potential partner protein. The prediction is based on features that can be calculated using the amino acid sequence alone. Proteus compares favorably with existing methods predicting twice as many true positives as the second best method (55% vs. 27%) with a much higher precision on an independent data set. The current study also sheds some light on a possible 'disorder-to-order' transitioning consensus, untangled, yet embedded in the amino acid sequence of IDPs. Some guidelines have also been suggested for proceeding with a real-life structural modeling involving an IDPR using Proteus.Software Availabilityhttps://github.com/bjornwallner/proteus

scholarly journals Hydrophobic residues advance the onset of simple coacervation in intrinsically disordered proteins at low densities: Insights from field theoretical simulations studies

2021 ◽  
Author(s):  
Satwik Ramanjanappa ◽  
Sahithya S. Iyer ◽  
Anand Srivastava
Keyword(s):  
Phase Separation ◽  
Intrinsically Disordered Proteins ◽  
Hydrophobic Interactions ◽  
Amino Acid Sequences ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Starting Point ◽  
Theoretical Simulations ◽  
The Way

AbstractIntrinsically disordered proteins (IDPs) have engendered a definitive change in the way we think about the classical “sequence-structure-function” dogma. Their conformational pliability and rich molecular recognition features endow them with the ability to bind to diverse partners and predispose them to an elaborate functional armory. And of late, with studies on IDP-based liquid-liquid phase separation (LLPS) leading to formation of functional subcellular coacervates - best described as “membrane-less organelles (MLOs)”, IDPs are also bringing about paradigmatic changes in the way we think about biomolecular assemblies and subcellular organization. Though it is well recognized that the phase behavior of a given IDP is tightly coupled to its amino-acid sequences, there are only a few theories to model polyampholyte coacervation for IDPs. Recently, Joan-Emma Shea and co-workers used field theoretical simulations (FTS) to elucidate the complete phase diagram for LLPS of IDPs by considering different permutations of 50-residues chain representing 25 Lysine and 25 Glutamic acid [1]. Our work is an extension of that FTS framework where we develop and solve an augmented Hamiltonian that also accounts for hydrophobic interactions in the chain. We show that incorporation of hydrophobic interactions result in an advanced onset of coacervation at low densities. The patterning of hydrophobic, positive and negative residues plays important role in determining relative differences in the onset of phase separation. Though still very coarse-grained, once additional chemical specificities are incorporated, these high throughput analytical theory methods can be used as a starting point for designing sequences that drive LLPS.

scholarly journals Relation between single-molecule properties and phase behavior of intrinsically disordered proteins

2018 ◽  
Vol 115 (40) ◽  
pp. 9929-9934 ◽  
Author(s):  
Gregory L. Dignon ◽  
Wenwei Zheng ◽  
Robert B. Best ◽  
Young C. Kim ◽  
Jeetain Mittal
Keyword(s):  
Phase Separation ◽  
Phase Behavior ◽  
Single Molecule ◽  
Intrinsically Disordered Proteins ◽  
Critical Role ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Phase Boundaries ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

Proteins that undergo liquid–liquid phase separation (LLPS) have been shown to play a critical role in many physiological functions through formation of condensed liquid-like assemblies that function as membraneless organelles within biological systems. To understand how different proteins may contribute differently to these assemblies and their functions, it is important to understand the molecular driving forces of phase separation and characterize their phase boundaries and material properties. Experimental studies have shown that intrinsically disordered regions of these proteins are a major driving force, as many of them undergo LLPS in isolation. Previous work on polymer solution phase behavior suggests a potential correspondence between intramolecular and intermolecular interactions that can be leveraged to discover relationships between single-molecule properties and phase boundaries. Here, we take advantage of a recently developed coarse-grained framework to calculate the θ temperatureTθ, the Boyle temperatureTB, and the critical temperatureTcfor 20 diverse protein sequences, and we show that these three properties are highly correlated. We also highlight that these correlations are not specific to our model or simulation methodology by comparing between different pairwise potentials and with data from other work. We, therefore, suggest that smaller simulations or experiments to determineTθorTBcan provide useful insights into the corresponding phase behavior.

scholarly journals Amino acid substitution scoring matrices specific to intrinsically disordered regions in proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rakesh Trivedi ◽  
Hampapathalu Adimurthy Nagarajaram
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Compositional Bias ◽  
Amino Acid Residues ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Scoring Matrices ◽  
Disordered Regions

Abstract An amino acid substitution scoring matrix encapsulates the rates at which various amino acid residues in proteins are substituted by other amino acid residues, over time. Database search methods make use of substitution scoring matrices to identify sequences with homologous relationships. However, widely used substitution scoring matrices, such as BLOSUM series, have been developed using aligned blocks that are mostly devoid of disordered regions in proteins. Hence, these substitution-scoring matrices are mostly inappropriate for homology searches involving proteins enriched with disordered regions as the disordered regions have distinct amino acid compositional bias, and therefore expected to have undergone amino acid substitutions that are distinct from those in the ordered regions. We, therefore, developed a novel series of substitution scoring matrices referred to as EDSSMat by exclusively considering the substitution frequencies of amino acids in the disordered regions of the eukaryotic proteins. The newly developed matrices were tested for their ability to detect homologs of proteins enriched with disordered regions by means of SSEARCH tool. The results unequivocally demonstrate that EDSSMat matrices detect more number of homologs than the widely used BLOSUM, PAM and other standard matrices, indicating their utility value for homology searches of intrinsically disordered proteins.

scholarly journals Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 114 ◽  
Author(s):  
Ucheor Choi ◽  
Hugo Sanabria ◽  
Tatyana Smirnova ◽  
Mark Bowen ◽  
Keith Weninger
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Conformational Dynamics ◽  
Thermal Fluctuations ◽  
Amino Acid Sequences ◽  
Conformational Space ◽  
Disordered Proteins ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Wide Range ◽  
Polymer Models

The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. However, the variability in interaction energy between different amino acid sequences provides the possibility that some configurations may be strongly preferred while others are forbidden. In compact globular IDPs, core hydration and packing density can vary between segments of the polypeptide chain leading to complex conformational dynamics. Here, we describe a growing number of proteins that appear intrinsically disordered by biochemical and bioinformatic characterization but switch between restricted regions of conformational space. In some cases, spontaneous switching between conformational ensembles was directly observed, but few methods can identify when an IDP is acting as a restricted chain. Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements. Thus, mapping the accessible energy landscape and capturing dynamics across a wide range of timescales are essential to recognize when an IDP is acting as such a switch.

scholarly journals Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

2021 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Akshatha Ganne ◽  
Meenakshisundaram Balasubramaniam ◽  
Robert J. Shmookler Reis
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Physiological Processes ◽  
Protein Partners ◽  
And Function ◽  
Computational Analyses ◽  
Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

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