scholarly journals The impact of O-glycan chemistry on the stability of intrinsically disordered proteins

2018 ◽  
Vol 9 (15) ◽  
pp. 3710-3715 ◽  
Author(s):  
Erica T. Prates ◽  
Xiaoyang Guan ◽  
Yaohao Li ◽  
Xinfeng Wang ◽  
Patrick K. Chaffey ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Glycosylation ◽  
Disordered Proteins ◽  
Biological Functions ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
P Protein ◽  
The Stability ◽  
The Impact

Protein glycosylation is a diverse post-translational modification that serves myriad biological functions.

scholarly journals The Distinct Properties of the Consecutive Disordered Regions Inside or Outside Protein Domains and Their Functional Significance

2021 ◽  
Vol 22 (19) ◽  
pp. 10677
Author(s):  
Huqiang Wang ◽  
Haolin Zhong ◽  
Chao Gao ◽  
Jiayin Zang ◽  
Dong Yang
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Domains ◽  
Comprehensive Analysis ◽  
Disordered Proteins ◽  
Functional Constraints ◽  
Biological Functions ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
And Function ◽  
Disordered Regions

The consecutive disordered regions (CDRs) are the basis for the formation of intrinsically disordered proteins, which contribute to various biological functions and increasing organism complexity. Previous studies have revealed that CDRs may be present inside or outside protein domains, but a comprehensive analysis of the property differences between these two types of CDRs and the proteins containing them is lacking. In this study, we investigated this issue from three viewpoints. Firstly, we found that in-domain CDRs are more hydrophilic and stable but have less stickiness and fewer post-translational modification sites compared with out-domain CDRs. Secondly, at the protein level, we found that proteins with only in-domain CDRs originated late, evolved rapidly, and had weak functional constraints, compared with the other two types of CDR-containing proteins. Proteins with only in-domain CDRs tend to be expressed spatiotemporal specifically, but they tend to have higher abundance and are more stable. Thirdly, we screened the CDR-containing protein domains that have a strong correlation with organism complexity. The CDR-containing domains tend to be evolutionarily young, or they changed from a domain without CDR to a CDR-containing domain during evolution. These results provide valuable new insights about the evolution and function of CDRs and protein domains.

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 The Effect of Multisite Phosphorylation on the Conformational Properties of Intrinsically Disordered Proteins

2021 ◽  
Vol 22 (20) ◽  
pp. 11058
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Salt Bridges ◽  
Intrinsically Disordered ◽  
Local Contraction ◽  
Charged Residues ◽  
Common Strategy ◽  
Disordered Peptides ◽  
Dynamics Simulations ◽  
The Impact

Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins have received increased attention in recent years, a full understanding of the conformational and structural implications of phosphorylation has not yet been achieved. Here, we present all-atom molecular dynamics simulations of five disordered peptides originated from tau, statherin, and β-casein, in both phosphorylated and non-phosphorylated state, to compare changes in global dimensions and structural elements, in an attempt to gain more insight into the controlling factors. The changes are in qualitative agreement with experimental data, and we observe that the net charge is not enough to predict the impact of phosphorylation on the global dimensions. Instead, the distribution of phosphorylated and positively charged residues throughout the sequence has great impact due to the formation of salt bridges. In statherin, a preference for arginine–phosphoserine interaction over arginine–tyrosine accounts for a global expansion, despite a local contraction of the phosphorylated region, which implies that also non-charged residues can influence the effect of phosphorylation.

scholarly journals Computational Prediction of Intrinsically Disordered Proteins Based on Protein Sequences and Convolutional Neural Networks

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Hao He ◽  
Yong Yang
Keyword(s):  
Neural Networks ◽  
Convolutional Neural Networks ◽  
Intrinsically Disordered Proteins ◽  
Prediction Method ◽  
Computational Prediction ◽  
Disordered Proteins ◽  
Biological Functions ◽  
Intrinsically Disordered ◽  
Central Residue

Intrinsically disordered proteins (IDPs) possess at least one region that lacks a single stable structure in vivo, which makes them play an important role in a variety of biological functions. We propose a prediction method for IDPs based on convolutional neural networks (CNNs) and feature selection. The combination of sequence and evolutionary properties is used to describe the differences between disordered and ordered regions. Especially, to highlight the correlation between the target residue and adjacent residues, multiple windows are selected to preprocess the protein sequence through the selected properties. The shorter windows reflect the characteristics of the central residue, and the longer windows reflect the characteristics of the surroundings around the central residue. Moreover, to highlight the specificity of sequence and evolutionary properties, they are preprocessed, respectively. After that, the preprocessed properties are combined into feature matrices as the input of the constructed CNN. Our method is training as well as testing based on the DisProt database. The simulation results show that the proposed method can predict IDPs effectively, and the performance is competitive in comparison with IsUnstruct and ESpritz.

scholarly journals Molecular Dynamics Simulations of Phosphorylated Intrinsically Disordered Proteins: A Force Field Comparison

2021 ◽  
Vol 22 (18) ◽  
pp. 10174
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Salt Bridges ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
The Difference ◽  
Disordered Peptides ◽  
Dynamics Simulations

Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are dependent on the accuracy of the force field used. Here, we compared the conformational ensembles produced by Amber ff99SB-ILDN+TIP4P-D and CHARMM36m, for four phosphorylated disordered peptides ranging in length from 14–43 residues. CHARMM36m consistently produced more compact conformations with a higher content of bends, mainly due to more stable salt bridges. Based on comparisons with experimental size estimates for the shortest and longest peptide, CHARMM36m appeared to overestimate the compactness. The difference between the force fields was largest for the peptide showing the greatest separation between positively charged and phosphorylated residues, in line with the importance of charge distribution. For this peptide, the conformational ensemble did not change significantly upon increasing the ionic strength from 0 mM to 150 mM, despite a reduction of the salt-bridging probability in the CHARMM36m simulations, implying that salt concentration has negligible effects in this study.

scholarly journals Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology

2019 ◽  
Vol 20 (1) ◽  
pp. 141 ◽  
Author(s):  
Francesca Longhena ◽  
Gaia Faustini ◽  
Maria Grazia Spillantini ◽  
Arianna Bellucci
Keyword(s):  
Lipid Membranes ◽  
Intrinsically Disordered Proteins ◽  
Lipid Membrane ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Monoamine Transporters ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Multiple Partners

Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein–protein and protein–lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

scholarly journals Information theoretic measures for quantifying sequence–ensemble relationships of intrinsically disordered proteins

2019 ◽  
Vol 32 (4) ◽  
pp. 191-202 ◽  
Author(s):  
Megan C Cohan ◽  
Kiersten M Ruff ◽  
Rohit V Pappu
Keyword(s):  
Intrinsically Disordered Proteins ◽  
De Novo ◽  
Disordered Proteins ◽  
Specific Sequence ◽  
Information Theoretic ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Information Theoretic Measures ◽  
Modulating Functions ◽  
The Impact

Abstract Intrinsically disordered proteins (IDPs) contribute to a multitude of functions. De novo design of IDPs should open the door to modulating functions and phenotypes controlled by these systems. Recent design efforts have focused on compositional biases and specific sequence patterns as the design features. Analysis of the impact of these designs on sequence-function relationships indicates that individual sequence/compositional parameters are insufficient for describing sequence-function relationships in IDPs. To remedy this problem, we have developed information theoretic measures for sequence–ensemble relationships (SERs) of IDPs. These measures rely on prior availability of statistically robust conformational ensembles derived from all atom simulations. We show that the measures we have developed are useful for comparing sequence-ensemble relationships even when sequence is poorly conserved. Based on our results, we propose that de novo designs of IDPs, guided by knowledge of their SERs, should provide improved insights into their sequence–ensemble–function relationships.

scholarly journals Structural and Energetic Characterization of the Denatured State from the Perspectives of Peptides, the Coil Library, and Intrinsically Disordered Proteins

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 634
Author(s):  
Elisia A. Paiz ◽  
Karen A. Lewis ◽  
Steven T. Whitten
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Cell Function ◽  
Thermodynamic Description ◽  
Disordered Proteins ◽  
Hydrodynamic Size ◽  
Sequence Dependence ◽  
Denatured State ◽  
Intrinsically Disordered ◽  
Heat Effects ◽  
The Impact

The α and polyproline II (PPII) basins are the two most populated regions of the Ramachandran map when constructed from the protein coil library, a widely used denatured state model built from the segments of irregular structure found in the Protein Data Bank. This indicates the α and PPII conformations are dominant components of the ensembles of denatured structures that exist in solution for biological proteins, an observation supported in part by structural studies of short, and thus unfolded, peptides. Although intrinsic conformational propensities have been determined experimentally for the common amino acids in short peptides, and estimated from surveys of the protein coil library, the ability of these intrinsic conformational propensities to quantitatively reproduce structural behavior in intrinsically disordered proteins (IDPs), an increasingly important class of proteins in cell function, has thus far proven elusive to establish. Recently, we demonstrated that the sequence dependence of the mean hydrodynamic size of IDPs in water and the impact of heat on the coil dimensions, provide access to both the sequence dependence and thermodynamic energies that are associated with biases for the α and PPII backbone conformations. Here, we compare results from peptide-based studies of intrinsic conformational propensities and surveys of the protein coil library to those of the sequence-based analysis of heat effects on IDP hydrodynamic size, showing that a common structural and thermodynamic description of the protein denatured state is obtained.

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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